Phytochemistry 174 (2020) 112332

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Phytochemistry
journal homepage: www.elsevier.com/locate/phytochem

Review

Acetogenins from Annonaceae family. Their potential biological T

applications
Adriana Neskea,∗, José Ruiz Hidalgoa, Nuria Cabedob,c, Diego Cortesb
a
Departamento de Química Orgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, 4000, San Miguel de Tucumán, Tucumán,
Argentina
b
Department of Farmacología, Facultad de Farmacia, Universidad de Valencia, 46100, Burjassot, Valencia, Spain
c
Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain

ARTICLE INFO ABSTRACT

Keywords: The aim of this contribution has been to continue with the knowledge about newly isolated acetogenins from
Annonaceous acetogenins Annonaceae family for the last fifteen years. This review will report classification, extraction, isolation, eluci-
Classification dation of the structure, biological activities and mechanism of action of such interesting natural products. In fact,
Extraction out of the 532 compounds reviewed, 115 previously non-described annonaceous acetogenins have been added to
Isolation
the list of isolated compounds from 2005 to May 2019.
Structure elucidation
Biological activities
Mechanism of action

1. Introduction
Annonaceous acetogenins (ACGs) constitute a series of polyketides
found almost exclusively in plants of the Annonaceae family, some of
their native species being important economic crops in Asia and North
and South America. Acetogenins are specialised metabolites derived
from the polyketide pathway; their potential role as chemotaxonomical
markers for red algae belonging to the Laurencia complex has long been
pointed out. C15 acetogenins from algae are quite different from plant
acetogenins because they are usually halogenated and have an enyne or
bromoallene terminal group. Since they were first reported, laurencin
and other algal acetogenins have inspired great curiosity not also
among natural product chemists but also among those working with
synthesis (Wanke et al., 2015).
ACGs are a unique class of C-35/C37 specialised metabolites derived
from long chain (C-32/C34) fatty acids in the polyketide pathway. They
are usually characterized by a combination of fatty acids with a 2-
propanol unit at C-2 that forms a methyl-substituted α,β-unsaturated γ-
lactone (Bermejo et al., 2005; Alali et al., 1999a). Since the discovery of
uvaricin from Uvaria accuminata Oliv. in 1982, numerous ACGs have
been isolated and identified from different parts of annonaceous plants,
especially the seeds by virtue of the advances in separation technology
(Tempesta et al., 1982; McLaughlin, 2008).
The isolation of ACGs has so far been reported in 16 genera of this
family, including Ampelocissus (1), Annona (20 species), Artabotrys (1),
Asimina (3), Cananga (1), Dasymaschalon (1), Disepalum (2),
Goniothalamus (5), Mitrephora (2), Ophrypetalum (1), Polyalthia (2),
Porcelia (1), Rollinia (7), Saccopetalum (1), Uvaria (9), and Xylopia (2).
Annonaceous acetogenins have been found to exhibit a broad range
of biological properties, such as antineoplastic, antiparasitic, cytotoxic,
immunosuppressive, neurotoxic, and pesticidal effects (Alali et al.,
1999a; Zafra-Polo et al., 1998). Among the broad array of biological
properties documented in biomedical literature for the ACGs, their
cytotoxic and antitumor effects and the underlying mechanisms for
such effects have received the most attention (Liaw et al., 2016).
Due to their special structures and extensive biological activities,
ACGs have attracted a lot of scientific interest for the last two decades.
The chemical structures of the major acetogenins are shown in Fig. 1.
Most importantly, organic chemists have overcome the challenges
of meeting the total and rapid synthesis of ACGs with multiple stereo-
centers for the last 15 years. Moreover, growing interest in investigating
the mechanisms of biochemical action of ACGs has been triggered by
recent advances in understanding the processes involved in tumor cell
death. Members of this class of natural compounds are considered to be
possible candidates for future anticancer drugs. Bioactivity and me-
chanism of action studies on ACGs have both focused on their potent
cytotoxicity against cancer cells and the inhibition of mitochondrial
respiratory chain complex I (Álvarez Colom et al., 2009; Barrachina

∗
Corresponding author.
E-mail addresses: adriananeske@hotmail.com, neskesan@gmail.com (A. Neske), dcortes@uv.es (D. Cortes).

https://doi.org/10.1016/j.phytochem.2020.112332
Received 19 June 2019; Received in revised form 28 February 2020; Accepted 2 March 2020
0031-9422/ © 2020 Elsevier Ltd. All rights reserved.
A. Neske, et al.
Fig. 1. General structure of acetogenins.
et al., 2004; Chahboune et al., 2006; Chih et al., 2001; Zafra-Polo et al.,
1996). However, recent studies have reported the relationship between
this type of compounds and sporadic neurodegenerative tau pathologies
in those humans who have ingested annonaceous plants containing
ACGs (Höllerhage et al., 2009; Champy, 2011).
The purpose of this contribution has been to continue with the
classification, extraction, isolation, structure elucidation and biological
activities of these types of compounds since 2005 (Bermejo et al.,
2005). Out of the 532 compounds reviewed, over 115 previously non-
described ACGs have been added to the list of isolated compounds, from
2005 to May 2019.
Phytochemical investigations and biological studies on different
parts of Annonaceae plants resulted in the identification of a wide array
of ACGs compounds, as summarized in Tables 1–11.
Classification is made following the same criteria and based on the
structural characteristics shown in Fig. 2. Three types of γ-lactone
moiety, L-B2 (α-acetonyl-α,β-unsaturated-γ-lactone), L-E (saturated γ-
hydroxy/methoxy methyl-γ-lactone) and L-F (β-methoxy-γ-methylene-
α,β-unsaturated-γ-butyrolactone), as well as the type of tetra-
hydropyran (THP) system (T-G.3) are included. Within the tables,
compounds are presented in chronological order of discovery. For a
complete revision, both non-described and previously published data
are reported. To make the reading of tables easier, multiple names for
ACGs (shown as, e.g. “narumicin-I or uvarigrandin-A) have only been
given when two research groups simultaneously isolated the com-
pound. The great number of compounds to be added made the inclusion
of new subgroups necessary and, in general, their numbers listed in the
previous review are maintained (Bermejo et al., 2005). The additional
non-described compounds are given in bold. The number of ‘reliable’
ACGs should be so far considered as 532, 63 of them being linear, 24
epoxy, 246 mono-THF, 190 bis-THF, 1 tri-THF, and 8 other ACGs be-
longing to the THP group (see Tables 1–11). Table 12 summarizes the
species from the Annonaceae family from which previously non-de-
scribed ACGs have been isolated. Two new genera, Ampelicissus (Pettit
et al., 2008) and Cananga (Wongsa et al., 2011) were found to contain
ACGs. In Table 13 the ACGs cited in this review are listed in alphabe-
tical order. In addition, a survey on the advances in the interaction with
liposomal membranes and bacterial biofilm promoters, as well as in the
neurotoxic and pesticidal activities in recent years, has been included.
2. Extraction, isolation and purification
The classic extraction of ACGs from plants is carried out by suc-
cessive solvent extractions with increasingly polar solvents, or by li-
quid/liquid partition from an initial alcoholic extract (Bermejo et al.,
2005). The separation of ACGs is then performed by chromatography
on silica gel or by preparative HPLC (Alali et al., 1999a; Zeng et al.,
1996a; Cavé et al., 1997a). Positional isomeric and epimeric ACGs have
been successfully separated by preparative HPLC. Countercurrent
chromatography (CCC or CPC) has also been used for isolating ACGs
(Duret et al., 1997b). This method is highly effective since large
amounts of mixtures and crude extracts, when purified by this method,
resulted in pure compounds. Again, positional isomers, epimers and
homologous ACGs have been successfully separated by CPC (Hopp
et al., 1999). Also, chiral HPLC has been used with success for the
2
Phytochemistry 174 (2020) 112332
separation of epimeric ACGs obtained by synthesis (Cecil et al., 2004),
which will allow in the future the determination of the absolute
configurations of natural ACGs.
However, the structures of ACGs were liable to change at more than
60 °C and their extraction yields were low when using the traditional
organic solvent extraction method. Yang et al. (2009b) reported that all
samples from Annona genus plant seeds were extracted by supercritical
carbon dioxide under optimized conditions. The established method
can be applied to evaluate the intrinsic quality of Annonaceae plant
seeds (Yang et al., 2009b). As an alternative of traditional extraction
methods, supercritical fluid CO2 extraction (SFE), an extraction tech-
nique under low temperature, has recently been used in the extraction
of bioactive constituents from herbal medicines for its small amount of
solvent consumption, automated sample handling and high extractive
effectiveness. A validated analytical method for qualification and
quantification of ACGs from different Annona plant seeds has been
developed, the new method was evaluated to be precise and accurate
and successfully applied to determine the contents of eight major ACGs
from five different Annona plant seeds. It was a convenient and precise
method to assess the quality of different Annonaceae plant seeds (Yang
et al., 2009b).
3. Structural elucidation
The structural elucidation of ACGs has already been summarized in
previous reviews (Alali et al., 1999a; Zeng et al., 1996a; Cavé et al.,
1997a). It consists of an analysis of the mass spectra to determine the
exact molecular formula, followed by EI-MS and FAB-MS, which allow
to determine the position of the functional groups on the alkyl chain.
Also, the ionization by electronic impact at 70 eV by the use of an ion
trap allows to observe the quasimolecular ion [MH]+ (Bermejo et al.,
2005). Often, the literature describes the use of soft ionization techni-
ques for the determination of the molecular weight of ACGs. The ion
trap detector is capable of producing, in some situations, quasi-mole-
cular ions when IE is being used. This is a frequently observed phe-
nomenon and is described in the literature as chemical autoionization
in ion trap detectors (Eichelberger et al., 1987). Chemical autoioniza-
tion is an intermolecular mass transfer phenomenon that produces the
quasimolecular ion [M+H]+, which is observed in ion storage mass
analyzers when the sample pressure increases or is subjected to pro-
longed confinement. The process is particularly favored for aliphatic
molecules containing heteroatoms. The formation of [M+H]+ is im-
portant when the alkyl fragments, whose conjugate bases have low
proton affinity, are present in abundance (Pannell et al., 1989).
Modern MS/MS approach has been introduced for the last years
including Maldi-TOF/TOF and ESI-MS/MS after lithium cationisation.
Collision-induced dissociation experiments of several acetogenins were
carried out under high and low collision energy conditions. Each
compound was studied as protonated or deprotonated and lithium- or
sodium-cationized molecules, using ElectroSpray Ionization (ESI) with
a hybrid linear trap/orbitrap mass spectrometer (LTQ-Orbitrap®). The
same ion species were studied with a Matrix-Assisted Laser Desorption
Ionization (MALDI) tandem mass spectrometer in a high collision en-
ergy regime (1 or 2 keV). Although each of the techniques showed some
limitations in the detection of functional groups, unambiguous
A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 1
Acetogenins without tetrahydrofuran rings: linear acetogenins (Group 1).
Olefinic position Hydroxyl positions Relative Molecular M+ Species [Ref]
configuration formula

Group 1a – Vicinal dihydroxylated and olefinic linear acetogenins (giganin type)

1a.1 giganin Δ13 4,10,17,18 c-th C35 H64 O6 580 G. giganteus (Fang et al., 1993)
1a.2 venezenin (CO,10) Δ21 4,17,18 th-c C37 H66 O6 606 X. aromatica (Colman-Saizarbitoria
et al., 1995)
1a.3 coriadienin Δ13; Δ17 4,10,21,22 c-c-th C37 H66 O6 606 A. coriacea (Meneses da Silva et al.,
1996)
1a.4 tonkinelin 17,18 th C37 H66 O4 578 U. tonkinesis (Chen and Yu, 1996a,
1996b)
1a.5 montecristin Δ17; Δ21 13,14 th-c-c C37 H66 O4 574 A. muricata (Gleye et al., 1997a)
1a.6 cohibin-A Δ19 15,16 th-c C35 H66 O4 548 A. muricata (Gleye et al., 1997b)
1a.7 cohibin-B Δ17 13,14 th-c C35 H64 O4 548 A. muricata (Gleye et al., 1997b)
1a.8 venezinone Δ21 10,17,18 th-c C37 H68 O6 608 X. aromatica (Colman-Saizarbitoria
et al., 1996)
1a.9 gardnerilin-A 4,8,15,16,19,20 th-th C35 H66 O8 614 G. gardneri (Chen et al., 1998a,
1998b)
1a.10 gardnerilin-B 4,10,17,18 th C35 H66 O6 582 G. gardneri (Chen et al., 1998a,
1998b)
1a.11 donhexocin 4,10,15,16,19,20 th-th C35 H66 O8 614 G. donnaiensis (Jiang et al., 1998c)
1a.12 donbutocin 4,10,15,16 th C35 H66 O8 582 G. donnaiensis (Jiang et al., 1998c)
1a.13 murihexol 4,10,15,16,19,20 th-er C35 H66 O8 614 A. muricata (Yu et al., 1998)
1a.14 annojahnin (CO,10) Δ21 17,18 th-c C37 H66 O5 590 A. jahnii (Colman-Saizarbitoria
et al., 1998)
1a.15 cohibin-C + D Δ21/19 17/15,18/16 th-c C37 H68 O4 576 A. muricata (Gleye et al., 2000a,
2000b)
A.nutans (Gleye et al., 2000a,
2000b)
1a.16 annodienin (CO,10) Δ17; Δ21 13,14 th C37 H64 O5 588 A. jahnii (Colman-saizarbitoria
et al., 1999)
1a.17 jahnonacin Δ21 4,10,17,18 th C37 H68 O6 608 A. jahnii (Colman-saizarbitoria
et al., 1999)
1a.18 muricatenol Δ14 4,10,18,19 c-th C37 H68 O6 608 A. muricata (De Yu et al., 2000)
1a.19 donhepocin +34-epi 4,10,15,16,19,20,34 th-th C35 H66 O9 630 G. donnaiensis (Jiang et al., 1998c)
1a.20 donnaienin-D + 34-epi (OAc-4), 10,15,16,19,20,34 th-th C37 H66 O10 672 G. donnaiensis (Jiang et al., 1998a,
1998b, 1998c)
1a.21 artemoin-A + B + C + D 19,20/17,18 th C35 H66 O4 550 A. atemoya (Chang et al., 1999)
1a.22 (+)-monhexocin 4,9,15,16,19,20 th-th C35 H66 O8 614 A. montana (Liaw et al., 2005)
1a.23 (−)-monhexocin 4,9,15,16,19,20 th-th C35 H66 O8 614 A. montana (Liaw et al., 2005)

Group 1b – Hydroxylated (or ketonic) linear acetogenins (reticulatamol type)

1b.1 reticulatamol 15 C35 H66 O3 534 A. reticulata (Thi Tam et al., 1994)
1b.2 reticulatamone (CO,15) C35 H64 O3 532 A. reticulata (Tam et al., 1995)
1b.3 longanin 4,10,18 C35 H66 O5 566 As. longifolia (Ye et al., 1996a,
1996b, 1996c, 1996d)

Group 1c – Olefinic and acetylenic linear acetogenins (non-hydroxylated) (muridienin-1 type)

1c.1 muridienin-1 Δ13; Δ17 c-c C35 H62 O2 514 A. muricata (Gleye et al., 1996)
1c.2 muridienin-2 Δ15; Δ19 c-c C37 H66 O2 542 A. muricata (Gleye et al., 1996)
1c.3 butyrolactone-1 Δ21; Δ13 (≡) C25 H42 O3 390 P. macrocarpa (Chaves and Roque,
1997)
1c.4 butyrolactone-2 Δ13 (≡) C25 H44 O3 392 P. macrocarpa (Chaves and Roque,
1997)
(continued on next page)

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 1 (continued)

Olefinic position Hydroxyl positions Relative Molecular M+ Species [Ref]

configuration formula

1c.5 chatenaytrienin-1 + 2 Δ13/11; Δ17/15; Δ21/19 C35 H60 O2 512 A. nutans, A. muricata (Gleye et al.,
1998c)
1c.6 chatenaytrienin-3 + 4 Δ13/15; Δ17/19; Δ21/23 C37 H64 O2 540 A. nutans, A. muricata (Gleye et al.,
1998c)
1c.7 muricadienin Δ15; Δ19 C35 H62 O2 514 A. nutans, A. muricata (Gleye et al.,
1998c)
1c.8 muridienin-3 + 4 Δ13/17; Δ17/21 C37 H66 O2 542 A. nutans, A. muricata (Gleye et al.,
1998c)
1c.9 goniothalamusin Δ13 (≡);Δ21 C25 H42 O3 390 G. gardneri (Seidel et al., 1999)
1c.10 saccopetrin-A Δ13 (≡);Δ21 C25 H42 O3 390 S. prolificum (Wang et al., 2002a,
2002b)
1c.11 saccopetrin-B Δ13 (≡);Δ21 (≡) C25 H40 O3 388 S. prolificum (Wang et al., 2002a,
2002b)
1c.12 artapetalin-A Δ9; Δ12; Δ15 c-c-c C22 H32 O3 344 Ar. hexapetalus (Wong and Brown,
2002)
1c.13 artapetalin-B Δ9; Δ12; Δ15 18 c-c-c C22 H32 O4 360 Ar. hexapetalus (Wong and Brown,
2002)
1c.14 artapetalin-C Δ9; Δ12; Δ15 18 c-c-c C37 H54 O4 562 Ar. hexapetalus (Wong and Brown,
2002)
1c.15 xymarginatin (CO,10) Δ15, Δ19 c-c C37H64O3 556 X. emarginata (Colman-
Saizarbitoria et al., 2009)

Group 1d – Bis-lactonic linear acetogenins (rollicosin type)

1d.1 rollicosin 4,15 C22 H36 O6 396 R. mucosa (Liaw et al., 2003)
1d.2 squamostolide 15 C22 H36 O5 380 A.squamosa (Xie et al., 2003)

Group 1e – Olefinic and acetylenic linear acetogenins (cananginone and mitregenin types)

1e.1 cananginone-A Δ11 (≡); Δ13 (≡); 15Z,19Z C24H34O3 370 C. latifolia (Wongsa et al., 2011)
Δ15, Δ19
1e.2 cananginone-B Δ11 (≡); Δ13 (≡); C24H36O3 372 C. latifolia (Wongsa et al., 2011)
Δ15
1e.3 cananginone-C Δ11 (≡); Δ13 (≡); C24H36O3 372 C. latifolia (Wongsa et al., 2011)
Δ19
1e.4 cananginone-D Δ11 (≡); Δ13 (≡) C24H38O3 374 C. latifolia (Wongsa et al., 2011)
1e.5 cananginone-E Δ11 (≡); Δ13; Δ19 C23H36O3 360 C. latifolia (Wongsa et al., 2011)
1e.6 cananginone-F Δ11 (≡); Δ19 C23H38O3 362 C. latifolia (Wongsa et al., 2011)
1e.7 cananginone-G Δ11 (≡); Δ19 C24H40O3 376 C. latifolia (Wongsa et al., 2011)
1e.8 cananginone-H Δ9 (≡); Δ11, Δ17 C21H32O3 332 C. latifolia (Wongsa et al., 2011)
1e.9 cananginone-I Δ9 (≡); Δ11 C21H34O3 334 C. latifolia (Wongsa et al., 2011)
1e.10 debilisone-A Δ13 (≡); Δ15 (≡) C25H40O3 388 P. debilis (Panthama et al., 2010)
1e.11 debilisone-B Δ13 (≡); Δ15 (≡) C25H40O4 404 P. debilis (Panthama et al., 2010)
1e.12 debilisone-C Δ13 (≡); Δ15 (≡), C25H38O3 386 P. debilis (Panthama et al., 2010)
Δ17
1e.13 debilisone-D Δ13 (≡); Δ15 (≡), C25H36O3 384 P. debilis (Panthama et al., 2010)
Δ17,Δ21
1e.14 debilisone-E Δ13 (≡); Δ15 (≡), C25H36O3 384 P. debilis (Panthama et al., 2010)
Δ17,Δ21
1e.15 debilisone-F Δ15 (≡); Δ17 (≡), C27H42O3 414 P. debilis (Panthama et al., 2010)
Δ19
1e.16 9,10-dihydrooropheolide Δ9, Δ11 (≡); Δ13 (≡), C21H28O3 328 M. glabra (Li et al., 2009)
Δ17
1e.17 mitregenin Δ9 (≡),Δ11 (≡),Δ13; C21H28O3 328 M. maingayi (Zhang et al., 2010)
Δ17
(continued on next page)

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 1 (continued)

Olefinic position Hydroxyl positions Relative Molecular M+ Species [Ref]

configuration formula

1e.18 oropheolide Δ9 (≡); Δ11 (≡); Δ13 C21H26O3 326 M. glabra (Li et al., 2009)
(≡), Δ17
1e.19 gracilipin-A Δ13 (≡); Δ15 (≡), 25 C25H36O3 384 G. gracilipes (Trieu et al., 2018)
Δ17,Δ21
1e.20 methylsaccopetrin-A Δ13 (≡), Δ21 C26H44O3 404 G. gracilipes (Trieu et al., 2018)

th = threo; c = cis. b G. = Goniothalamus; X. = Xylopia; A. = Annona; U. = Uvaria; As. = Asimina; P. = Porcelia; S. = Saccopetalum; Ar. = Artabotrys.

Table 2
Acetogenins without tetrahydrofuran rings: epoxy-acetogenins (groups 2–4).
a
Olefinic position Epoxy positions Molecular formula M+ Species [Ref]

Group 2– Mono-epoxy olefinic acetogenins (epoxymurin-A type)

2.1 epoxymurin-A Δ19 15,16 C35 H62 O3 530 A. muricata (Hisham et al., 1993)
or epomuricenin-A A. muricata (Roblot et al., 1993)
2.2 epoxymurin-B Δ15 19,20 C35 H62 O3 530 A. muricata (Hisham et al., 1993)
2.3 epomuricenin-B Δ17 13,14 C35 H62 O3 530 A. muricata (Roblot et al., 1993)
2.4 epomusenin-A Δ21 17,18 C37 H66 O3 558 R. mucosa (Chen et al., 1996a, 1996b)
2.5 epomusenin-B Δ19 15,16 C37 H66 O3 558 R. mucosa (Chen et al., 1996a, 1996b)
2.6 sabadelin Δ13 17,18 C35 H62 O3 530 A. muricata (Gleye et al., 1999)
2.7 epomurinin-A 15,16 C35 H64 O3 532 A. muricata (Melot et al., 2009)
2.8 epomurinin-B 13,14 C35 H64 O3 532 A. muricata (Melot et al., 2009)
2.9 neo-epoxyrolin Δ6 18,19 C36 H64 O3 544 A. squamosa (Li et al., 2010)
2.10 epoxyrolin-B 18,19 C36 H66 O3 546 A. squamosa (Li et al., 2010)

Group 3– Bis-epoxy acetogenins (diepomuricanin-A type)

3.1 diepomuricanin-Ab 15,16,19,20 C35 H62 O4 546 A. muricata (Laprévote et al., 1992)
3.2 corepoxylone (CO,10) 15,16,19,20 C35 H60 O5 560 A. muricata (Gromek et al., 1993)
3.3 dieporeticanin-1 17,18,21,22 C37 H66 O4 574 A. reticulata (Tam et al., 1994)
3.4 dieporeticanin-2 19,20,23,24 C37 H66 O4 574 A. reticulata (Tam et al., 1994)
3.5 dieporeticenin Δ23 15,16,19,20 C37 H64 O4 572 A. reticulata (Tam et al., 1994)
3.6 diepoxymontin 11,12,13,14 C35 H62 O4 546 A. montana (Wu et al., 1994)
3.7 diepomuricanin-B 17,18,21,22 C35 H62 O4 546 R. membranacea (Sahpaz et al., 1997)
3.8 diepoxyrollin 15,16,19,20 C37 H66 O4 574 R. membranacea (Sahpaz et al., 1997)
3.9 coronin Δ21 13,14,17,18 C37 H64 O4 572 A. muricata (Gleye et al., 2001)
3.10 dieposabadelin 13,14,17,18 C35 H62 O4 546 A. squamosa (Bajin ba Ndob et al., 2009)
3.11 squamocenin-A Δ23 15,16,19,20 C35 H60 O4 544 A. squamosa (Bajin ba Ndob et al., 2009)
3.12 annopurpuricin-E Δ18 12,13,14,15 C37 H66 O4 574 A. purpurea (Hernández-Fuentes et al., 2019)

Group 4– Tri-epoxy acetogenins (tripoxyrollin type)

4.1 tripoxyrollin 15,16,19,20,23,24 C37 H64 O5 588 R. membranacea (Sahpaz et al., 1993)

a a
A. = Annona; R. = Rollinia.
b
Mixture of syn- and anti-diepomuricani -A.

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 3
Mono-THF α,α'-dihydroxylated γ-lactone acetogenins (Groups 5–8).
a b
Hydroxyl positions Relative configuration of Molecular formula M+ Species [Ref]
THF

Group 5– Dihydroxylated acetogenins (uvariamicin-I type)

5.1 uvariamicin-I 15,20 th/t/th C37 H68 O5 592 U. narum (Hisham et al., 1990)
5.2 uvariamicin-II 17,22 th/t/th C37 H68 O5 592 U. narum (Hisham et al., 1990)
or reticulatacin A. reticulata (Saad et al., 1991)
5.3 uvariamicin-III 19,24 th/t/th C37 H68 O5 592 U. narum (Hisham et al., 1990)
5.4 solamin 15,20 th/t/th C35 H64 O5 564 A. muricata (Myint et al., 1991)
5.5 uvariamicin-IV 13,18 th/t/th C37 H68 O5 592 A. bullata (Hui et al., 1992)
5.6 bullatencin (Δ23) 15,20 th/t/th C37 H66 O5 590 A. bullata (Hui et al., 1992)
5.7 reticulatain-1 17,22 th/t/er C37 H68 O5 592 A. reticulata (Tam et al., 1995)
5.8 reticulatain-2 19,24 th/t/er C37 H68 O5 592 A. reticulata (Tam et al., 1995)
5.9 annotemoyin-1 17,22 th/t/th C35 H64 O5 564 A. atemoya (Duret et al., 1996)
5.10 annotemoyin-2 17,22 th/t/er C35 H64 O5 564 A. atemoya (Duret et al., 1996)
5.11 cis-solamin 15,2 th/c/th C35 H64 O5 564 A. muricata (Gleye et al., 1998a)
5.12 cis-panatellin 13,18 th/c/th C35 H64 O5 564 A. muricata (Gleye et al., 1998a)
5.13 cis-uvariamicin-IV 13,18 th/c/th C37 H68 O5 592 A. muricata (Gleye et al., 1998a)
5.14 cis-uvariamicin-I 15,2 th/c/th C37 H68 O5 592 A. muricata (Gleye et al., 1998a)
5.15 cis-reticulatacin 17,22 th/c/th C37 H68 O5 592 A. muricata (Gleye et al., 1998a)
5.16 laurifolin 19,24 th/t/th C35 H64 O5 564 R. laurifolia (Santos Pimenta et al., 2001)
c
5.17 15-palmitoylsolamin 15-palmitic,20 C51 H94 O6 802 A. muricata (Gleye et al., 1998b)
c
5.18 15-oleylsolamin 15-oleic,20 C53 H96 O6 828 A. muricata (Gleye et al., 1998b)
5.19 cis-bullatencin (Δ23) 15,20 th/c/th C37 H66 O5 590 U. chamae (Fall et al., 2002)
5.20 cis-annotemoyin-1 17,22 th/c/th C35 H64 O5 564 A. squamosa (Liaw et al., 2008)
5.21 dotistenin Δ23,15,20 th/t/er C35 H62 O5 562 A. squamosa (Bajin ba Ndob et al., 2009)
5.22 lepirenin Δ23,15,20 th/t/th C35 H62 O5 562 A. squamosa (Bajin ba Ndob et al., 2009)
5.23 squafosacin-F 15,20 th/c/er C35 H64 O5 564 A. squamosa (Liaw et al., 2008)
5.24 squafosacin-G 19,24 th/c/er C37 H68 O5 592 A. squamosa (Liaw et al., 2008)
5.25 squamocenin-B Δ25, 17,22 th/t/er C35 H62 O5 562 A. squamosa (Yu et al., 2005)

Group 6– Trihydroxylated and dihydroxylated ketonic acetogenins (murisolin type)

6.1 murisolin 4,15,20 th/t/th C35 H64 O6 580 A. muricata (Myint et al., 1990)
6.2 corossolin 10,15,20 th/t/th C35 H64 O6 580 A. muricata (Cortes et al., 1991a, 1991b, 1991c)
6.3 corossolone (CO,10) 15,20 th/t/th C35 H62 O6 578 A. muricata (Cortes et al., 1991a, 1991b, 1991c)
6.4 giganenin (Δ9) 13,18,21 th/t/th C37 H66 O6 606 G. giganteus (McLaughlin et al., 1992)
6.5 asiminenin-A (Δ23) 4,15,20 th/c/th C37 H66 O6 606 As. triloba (Woo et al., 1995a)
6.6 asiminenin-B (Δ23) 4,15,20 th/t/th C37 H66 O6 606 As. triloba (Woo et al., 1995a)
6.7 cis-murisolin 4,15,20 th/c/th C35 H64 O6 580 As. triloba (Woo et al., 1995b)
6.8 murisolin-A 4,15,20 th/t/er C35 H64 O6 580 As. triloba (Woo et al., 1995b)
6.9 uvarigranin 15, (OAc-17),22 er/t/th C39 H70 O7 650 U. grandiflora (Pan and Yu, 1995)
6.10 tonkinecin 5,17,22 th/t/th C37 H68 O6 608 U. tonkinesis (Chen and Yu, 1996a, 1996b)
6.11 longifolicin 10,13,18 th/t/th C35 H64 O6 580 As. longifolia (Ye et al., 1996a, 1996b, 1996c, 1996d)
6.12 longicoricin 10,15,20 th/t/th C37 H68 O6 608 As. longifolia (Ye et al., 1996a, 1996b, 1996c, 1996d)
6.13 4-deoxyannomontacin 10,17,22 th/t/th C37 H68 O6 608 G. giganteus (Alali et al., 1997a, 1997b)
6.14 4-deoxyannoreticuin 9,15,20 th/t/th C35 H64 O6 580 A. squamosa (Hopp et al., 1998a, 1998b)
6.15 cis-4-deoxyannoreticuin 9,15,20 th/c/th C35 H64 O6 580 A. squamosa (Hopp et al., 1998a, 1998b)
6.16 cis-reticulatacin-10-one (CO,10) 17,22 th/c/th C37 H66 O6 606 A. muricata (Gleye et al., 1998a)
6.17 calamistrin-A 15,17,22 th/t/er C37 H68 O6 608 U. calamistrata (Zhou et al., 1999)
6.18 calamistrin-B 15, (OAc-17),22 th/t/er C39 H70 O7 650 U. calamistrata (Zhou et al., 1999)
6.19 glaucabellin 4,17,22 th/t/er C37 H68 O6 608 A. glauca (Waechter et al., 1998)
6.20 uvarigrin 15,17,22 th/t/th C37 H68 O6 608 U. grandiflora (Pan and Yu, 1997)
6.21 calamistrin-C 13,19,24 th/t/th C37 H68 O6 608 U. calamistrata (Zhou et al., 2000)
6.22 calamistrin-D 13,19,24 th/t/er C37 H68 O6 608 U. calamistrata (Zhou et al., 2000)
6.23 calamistrin-E (Δ23) 5,15,20 /t/th C37 H66 O6 606 U. calamistrata (Zhou et al., 2000)
6.24 montalicin-A 4,13,18 th/t/th C33 H60 O6 552 A. montana (Liaw et al., 2004a)
6.25 montalicin-B 4,13,18 th/t/th C35 H64 O6 580 A. montana (Liaw et al., 2004a)
6.26 uvaribonianin 13, (OAc-15),20 er/t/th C37 H66 O8 644 U. boniana (Qin et al., 1996)
6.27 squamoxinone-D Δ7, 4,12,17 th/t/th C37 H66 O6 606 A. squamosa (Miao et al., 2016b)
6.28 cis-corossolone (CO,10) 15,20 th/c/th C35 H62 O6 578 A. muricata (Liaw et al., 2002)
6.29 plagionicin-B (CO,10) 5,15,20 th/t/th C35 H62 O7 594 D. plagioneurum (Éparvier et al., 2006)
6.30 squafosacin-C 11,17,22 th/t/th C35 H64 O6 580 A. squamosa (Liaw et al., 2008)
6.31 22-epi-calamistrin-B 15, (OAc-17),22 th/t/th C39 H70 O7 650 Ampelocissus sp. (Pettit et al., 2008)
6.32 squamocin-V 4,17,22 th/t/th C38 H70 O6 622 A. squamosa (Miao et al., 2016a)

Group 7– Tetrahydroxylated and trihydroxylated ketonic acetogenins

Group 7a – With OH at C4 (annonacin type)
7a.1 annonacin 4,10,15,20 th/t/th C35 H64 O7 596 A. densicoma (McCloud et al., 1987)
(continued on next page)

6
A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 3 (continued)
a b
Hydroxyl positions Relative configuration of Molecular formula M+ Species [Ref]
THF

7a.2 goniothalamicin 4,10,13,18 th/t/th C35 H64 O7 596 G. giganteus (Seidel et al., 1999)
7a.3 annonacinone (CO,10) 4,15,20 th/t/th C35 H62 O7 594 A. densicoma (Xu et al., 1989a, 1989b)
7a.4 annonacin-A 4,10,15,20 th/t/er C35 H64 O7 596 A. squamosa (Lieb et al., 1990)
7a.5 annomontacin 4,10,17,22 th/t/th C37 H68 O7 624 A. montana (Jossang et al., 1991)
7a.6 annoreticuin 4,9,15,20 th/t/th C35 H64 O7 596 A. reticulata (Wu et al., 1992)
7a.7 annoreticuinone (CO,9) 4,15,20 th/t/th C35 H62 O7 594 A. reticulata (Chan et al., 1993)
7a.8 xylopianin 4,8,15,20 th/t/th C35 H64 O7 596 X. aromatica, A. senegalensis (Colman-Saizarbitoria
et al., 1994b)
7a.9 xylopiacin 4,8,15,20 th/t/th C37 H68 O7 624 X. aromatica, A. senegalensis (Colman-Saizarbitoria
et al., 1994b)
7a.10 xylomaticin 4,10,15,20 th/t/th C37 H68 O7 624 X. aromatica, A. senegalensis (Colman-Saizarbitoria
et al., 1994b)
7a.11 reticulacinone (CO,11) 4,15,20 th/t/th C35 H62 O7 594 A. reticulata (Hisham et al., 1994)
7a.12 squamosten-A (Δ23) 4,12,15,20 th/t/th C37 H66 O7 622 A. squamosa (Araya et al., 1994a, 1994b)
7a.13 gonionenin (Δ21) 4,10,13,18 th/t/th C37 H66 O7 622 G. giganteus (Gu et al., 1994d)
7a.14 xylopien (Δ23) 4,8,15,20 th/t/th C37 H66 O7 622 X. aromatica, A. senegalensis (Colman-Saizarbitoria
et al., 1994a)
7a.15 xylomatenin (Δ23) or annogalene 4,10,15,20 th/t/th C37 H66 O7 622 X. aromatica, A. senegalensis (Colman-Saizarbitoria
et al., 1994a; Sahpaz et al., 1996)
7a.16 annosenegalin 4,10,15,20 th/t/er C37 H68 O7 624 A. senegalensis (Sahpaz et al., 1996)
7a.17 longicin 4,10,13,18 th/t/er C35 H64 O7 596 As. longifolia (Ye et al., 1995)
7a.18 annomutacin 4,10,17,22 th/t/er C37 H68 O7 624 A. muricata (Wu et al., 1995d)
7a.19 cis-annonacin 4,10,15,20 th/c/th C35 H64 O7 596 A. muricata (Rieser et al., 1996)
7a.20 cis-annonacinone (CO,10) 4,15,20 th/c/th C35 H62 O7 594 A. muricata (Rieser et al., 1996)
7a.21 cis-goniothalamicin 4,10,13,18 th/c/th C35 H64 O7 596 A. muricata (Rieser et al., 1996)
7a.22 arianacin + javoricin 4,12,15,20 th/t/th C35 H64 O7 596 A. muricata (Rieser et al., 1996)
7a.23 rollinecin-A + B 4,14,17,22 th/t/er C37 H68 O7 624 R. mucosa (Shi et al., 1996c)
7a.24 4-acetylannonacin (OAc-4), 10,15,20 th/t/th C37 H66 O7 638 As. longifolia (Ye et al., 1996a, 1996b, 1996c, 1996d)
7a.25 4-acetylxylomaticin (OAc-4), 10,15,20 th/t/th C39 H70 O8 666 As. longifolia (Ye et al., 1996a, 1996b, 1996c, 1996d)
7a.26 disepalin 4,10,15,OAc-20 th/t/th C39 H70 O8 666 D. anomalum (Ee et al., 1996)
7a.27 mosin-B (CO,9) 4,15,20 th/t/er C35 H62 O7 594 A. squamosa (Hopp et al., 1997)
7a.28 mosin-C (CO,9) 4,15,20 th/c/th C35 H62 O7 594 A. squamosa (Hopp et al., 1997)
7a.29 glacin-A 4,12,17,22 th/t/th C35 H64 O7 596 A. glabra (Liu et al., 1998a, 1998b)
7a.30 glacin-B 4,12,15,20 th/t/er C35 H64 O7 596 A. glabra (Liu et al., 1998a, 1998b)
7a.31 goniotetracin 4,10,13,18 th/t/th C37 H68 O7 624 G. giganteus (Alali et al., 1998a, 1998b)
7a.32 asitrilobin-A 4,10,17,22 thd/c/erd C37 H68 O7 624 As. triloba (Woo et al., 1999b)
7a.33 asitrilobin-B 4,10,15,20 thd/c/erd C35 H64 O7 596 As. triloba (Woo et al., 1999b)
7a.34 annoglacin-A 4,12,17,22 th/t/er C37 H68 O7 624 A. glabra (Liu et al., 1999a)
7a.35 annoglacin-B 4,12,17,22 th/t/th C37 H68 O7 624 A. glabra (Liu et al., 1999a)
7a.36 annocherin (CO,7) 4,15,20 th/t/th C35 H62 O7 594 A. cherimolia (Woo et al., 1999a)
7a.37 anmontanin-A (CO,8) 4,15,20 th/t/th C35 H62 O7 594 A. montana (Mootoo et al., 2000)
7a.38 rolliacocin 4,11,15,20 th/t/th C35 H64 O7 596 R. mucosa (Liaw et al., 1999a, 1999b)
7a.39 cis-annomontacin 4,10,17,22 th/c/th C37 H68 O7 624 A. muricata (Liaw et al., 2004b)
7a.40 annocherimolin (Δ21) 4,9,13,18 th/t/th C37 H66 O7 622 A. cherimolia (Kim et al., 2001c)
7a.41 asitrocin 4,12,15,20 er/t/th C35 H64 O7 596 As. triloba (Kim et al., 2000)
7a.42 muricin-G (Δ23) or annomocherin 4,10,15,20 th/t/th C35 H62 O7 594 A. muricata (Kim et al., 2001a, 2001b)
7a.43 asitrilobin-C 4,15,17,22 th/t/th C37 H68 O7 624 As. triloba (Woo et al., 2000)
7a.44 montalicin-C 4,7,13,18 th/t/th C35 H64 O7 596 A. montana (Liaw et al., 2004a)
7a.45 montalicin-D 4,11,13,18 th/t/th C35 H64 O7 596 A. montana (Liaw et al., 2004a)
7a.46 cis-annoreticuin 4,9,15,20 th/c/th C35 H64 O7 596 A. montana (Liaw et al., 2004a)
7a.47 montalicin-E 4,7,13,18 th/t/th C37 H66 O7 622 A. montana (Liaw et al., 2004a)
7a.48 montalicin-F 4,9,15,20 th/t/er C35 H64 O7 596 A. montana (Liaw et al., 2004a)
7a.49 montalicin-I 4,9,15,20 th/t/th C37 H68 O7 624 A. montana (Liaw et al., 2004a)
7a.50 montalicin-J 4,11,17,22 th/c/th C37 H68 O7 624 A. montana (Liaw et al., 2004a)
7a.51 annonamuricin-B 4,12,17,22 th/t/th C35 H64 O7 596 A. muricata (Sun et al., 2017)
7a.52 annonamuricin-C 4,12,17,21 th/t/th C35 H64 O7 596 A. muricata (Sun et al., 2017)
7a.53 annonamuricin-D 4,7,15,20 th/t/th C35 H64 O7 596 A. muricata (Sun et al., 2017)
7a.54 muricin-N 4,14,16,21 th/t/th C35 H64 O7 596 A. muricata (Sun et al., 2016)
7a.55 muricenin (Δ21) 4,10,13,18 th/t/th C37 H66 O7 622 A. muricata (Sun et al., 2016)
7a.56 muricin-J 4,13,15,20 th/t/er C35 H64 O7 596 A. muricata (Sun et al., 2014)
7a.57 muricin-K 4,12,17,25 th/t/th C35 H64 O7 596 A. muricata (Sun et al., 2014)
7a.58 squamosten-B 4,10,17,22 th/t/th C35 H64 O7 596 A. squamosa (Ma et al., 2019)

Group 7b – Without OH at C4 (plagionicin-A type)

7b.1 plagionicin-A 5,10,15,20 th/t/th C35 H64 O7 596 P. plagioneura (Zheng et al., 1994)
7b.2 tonkinin-A (CO,5) 15,17,22 th/t/er C37 H66 O7 622 U. tonkinesis (Chen et al., 1996a, 1996b)
7b.3 tonkinin-B (CO,5) 15,17,22 th/t/th C37 H66 O7 622 U. tonkinesis (Chen et al., 1996a, 1996b)
7b.4 tonkinin-C (CO,5) 15, (OAc-17),22 th/t/er C39 H68 O8 664 U. tonkinesis (Chen et al., 1996a, 1996b)
7b.5 tonkinesin-A 5,15,17,22 th/t/er C37 H68 O7 624 U. tonkinesis (Chen et al., 1996a, 1996b)
7b.6 tonkinesin-B 5,15,17,22 th/t/th C37 H68 O7 624 U. tonkinesis (Chen et al., 1996a, 1996b)
7b.7 tonkinesin-C 5,15, (OAc-17),22 th/t/er C39 H70 O8 666 U. tonkinesis (Chen et al., 1996a, 1996b)
7b.8 gigantransenin-A + B (Δ21) 10,13,18,23 th/t/th C37 H66 O7 622 G. giganteus (Zeng et al., 1996a, 1996b, 1996c,
1996d)
(continued on next page)

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 3 (continued)
a b
Hydroxyl positions Relative configuration of Molecular formula M+ Species [Ref]
THF

7b.9 gigantransenin-C (Δ22) 10,13,18,21 th/t/th C37 H66 O7 622 G. giganteus (Zeng et al., 1996a, 1996b, 1996c,
1996d)
7b.10 sootepensin-A 5,15, (OAc-17),22 th/c/er C39 H70 O8 666 Ds. sootepense (Sinz et al., 1998)
7b.11 sootepensin-Be (CO,5) 15, (OAc-17),22 th/t/th C39 H68 O8 664 Ds. sootepense (Sinz et al., 1998)
7b.12 asitrilobin-D 10,17,19,24 th/t/th C37 H68 O7 624 As. triloba (Woo et al., 2000)
7b.13 uvaribonin 5,15, (OAc-17),22 er/t/th C39 H70 O8 666 U. boniana (Qin et al., 1996)
7b.14 plagionicin-D (CO,5) 10,11,15,20 th/t/th C35 H62 O8 610 D. plagioneurum (Éparvier et al., 2006)
7b.15 plagioneurin-A 10, (OAc-15),17,22 th/t/th C39 H70 O8 666 D. plagioneurum (Éparvier et al., 2006)
7b.16 plagioneurin-B 10, (OAc-15),17,22 th/t/er C39 H70 O8 666 D. plagioneurum (Éparvier et al., 2006)
7b.17 plagioneurin-C (CO,10) (OAc-15),17,22 th/t/th C39 H70 O8 666 D. plagioneurum (Éparvier et al., 2006)
7b.18 plagioneurin-D (CO,10) 5, (OAc-15),17,22 th/t/th C39 H68 O9 680 D. plagioneurum (Éparvier et al., 2006)
7b.19 plagioneurin-E (CO,10) 5(OAc-15),17,22 th/t/th C39 H68 O9 680 D. plagioneurum (Éparvier et al., 2006)
7b.20 squafosacin-B 15,20,27,28 th/t/th-th C37 H68 O7 624 A. squamosa (Liaw et al., 2008)

Group 8– Polyhydroxylated and tetrahydroxylated ketonic acetogenins (annomonicin type)

8.1 annomonicin 4,8,13,15,20 th/t/th C35 H64 O8 612 A. montana (Jossang et al., 1990)
8.2 montanacin 4,8,13,19,24 th/t/th C37 H68 O8 640 A. montana (Jossang et al., 1990)
8.3 8-OH-annonacin 4,8,10,15,20 th/t/th C35 H64 O8 612 A. densicoma (Yu et al., 1992)
8.4 annomuricin-A 4,10,11,15,20 th-th/t/er C35 H64 O8 612 A. muricata (Wu et al., 1995a)
8.5 annomuricin-B 4,10,11,15,20 er-th/t/er C35 H64 O8 612 A. muricata (Wu et al., 1995a)
8.6 muricatin-C (CO,10) 4,15,20,25 th/t/th C35 H62 O8 610 A. muricata (Li et al., 1994)
8.7 muricatocin-A 4,10,12,15,20 ps er-th/t/th C35 H64 O8 612 A. muricata (Wu et al., 1995b)
8.8 muricatocin-B 4,10,12,15,20 ps er-th/t/er C35 H64 O8 612 A. muricata (Wu et al., 1995b)
8.9 muricatocin-C 4,10,12,15,20 ps th-th/t/er C35 H64 O8 612 A. muricata (Wu et al., 1995c)
8.10 annomuricin-C 4,10,11,15,20 th-th/t/th C35 H64 O8 612 A. muricata (Wu et al., 1995c)
8.11 annohexocin 4,8,10,12,15,20 th/t/er C35 H64 O9 628 A. muricata (Zeng et al., 1995a, 1995b)
8.12 muricatalicin 4,7,13,15,20 th/t/th C35 H64 O8 612 A. muricata (Gui and Yu, 1996)
8.13 coriaheptocin-A 4,7,12,14,16,19,20 er/t/th-an-th C35 H64 O10 644 A. coriacea (Meneses Da Silva et al., 1997)
8.14 coriaheptocin-B 4,7,12,14,16,19,20 th/t/th-an-th C35 H64 O10 644 A. coriacea (Meneses Da Silva et al., 1997)
8.15 donnaieninf 4,10,13,15,18 th-(th)-t,th C35 H64 O8 612 G. donnaiensis (Jiang et al., 1998a, 1998b, 1998c)
8.16 annomuricin-E 4,10,11,15,20 er-th/t/th C35 H64 O8 612 A. muricata (Kim et al., 1998a, 1998b)
8.17 muricapentocin 4,8,12,15,20 th/t/th C35 H64 O8 612 A. muricata (Kim et al., 1998a, 1998b)
8.18 araticin 15,20,23,24,28 er-th/t/th C37 H68 O8 640 A. spinescens (Queiroz et al., 1999a, 1999b)
8.19 annoglaxin (CO,12) 8,15,20,22 th/t/th C35 H62 O8 610 A. glabra (Liu et al., 1999b)
8.20 anmontanin-B (CO,10) 4,8,17,22 th/c/th C35 H62 O8 610 A. montana (Mootoo et al., 2000)
8.21 montanacin-B (CO,10) 4,8,15,20 th/t/th C35 H62 O8 610 A. montana (Wang et al., 2000)
8.22 montanacin-C (CO,10) 4,8,15,20 th/c/th C35 H62 O8 610 A. montana (Wang et al., 2000)
8.23 annoheptocin-A 4,9,14,16,21,22 er/t/th C37 H68 O10 672 A. coriacea (Meneses da Silva et al., 1998)
8.24 annoheptocin-B 4,9,14,16,21,22 th/t/th C37 H68 O10 672 A. coriacea (Meneses da Silva et al., 1998)
8.25 muricatatin-C (CO,10) 4,15,20,25 th/t/th C35 H66 O8 614 A. muricata (Li et al., 1994)
8.26 montacin (CO,7) 4,9,20,25 th/t/th C35 H62 O8 610 A. montana (Liaw et al., 2004b)
8.27 cis-montacin (CO,7) 4,9,20,25 th/c/th C35 H62 O8 610 A. montana (Liaw et al., 2004b)
8.28 montalicin-G 4,7,9,15,20 th/t/th C35 H64 O8 612 A. montana (Liaw et al., 2005)
8.29 montalicin-H 4,7,9,15,20 th/c/th C35 H64 O8 612 A. montana (Liaw et al., 2005)
8.30 plagionicin-C 4,5,11,15,20 th/c/th C35 H64 O8 612 D. plagioneurum (Éparvier et al., 2006)
8.31 squadiolin-A 15,16,19,24,28 th-th/t/er C37 H68 O8 640 A. squamosa (Liaw et al., 2008)

a
th = threo; er = erythro; t = trans; c = cis; ps = pseudo; an = anti.
b
U. = Uvaria; A. = Annona; G. = Goniothalamus; As. = Asimina; X. = Xylopia; P. = Polyalthia; R. = Rollinia; D. = Disepalum; Ds. = Dasymaschalon.
c
The relative configuration of compounds 5.17 and 5.18 was not determined by the authors.
d
For 7.32 and 7.33 the relative configurations are either th/t/er or er/t/th.

structural identification of acetogenins was obtained. MALDI-TOF/TOF
has the advantage over ESI-based methods to provide mass spectra rich
in informative fragments which allows the confirmation of some func-
tional group position. By contrast, ESI-LTQ-Orbitrap® analysis has the
advantage over MALDI that the mass spectra are relatively simple with
only fragments close to the functional groups. However, this technique
needs to carry out experiments both in the negative and positive ioni-
zation modes (Allegrand et al., 2010).
An innovative approach, using reversed-phase high-performance
liquid chromatography coupled to a hybrid linear ion trap/orbitrap
mass spectrometer (LTQ-Orbitrap®), was performed. Sensitivity was
enhanced by post-column infusion of lithium, since ACGs have a high
affinity for this cation. High level of structural information was ob-
tained from low-energy-collision-induced dissociation fragmentation
experiments of lithium-cationized ACGs ([M+ Li]+ ions). The sensi-
tivity, mass accuracy and specific fragmentation patterns proved to be
particularly useful for characterization of the ACGs whithin a crude
extract. This type of instrument is of great interest for structural
elucidation according to its high mass accuracy (below 2 ppm) and high
mass resolution (up to 100 000). HR-MS/MS and MS3 studies allow
unambiguous attribution of the main structural features of most com-
pounds, i.e. lactone type, THF pattern, number of other oxygenated
groups and positions of those bearing an impact on biological activity.
Redundant MS/MS spectra exemplify the diversity of enantiomers
within this class of natural compounds. More interestingly, sensitivity
and specificity of the method offer a new insight into the composition of
Annonaceae plants and reveal an unexpected diversity of ACGs within a
single extract, as well as within the class itself (Le Ven et al., 2012).
Acetogenins occurrence as complex mixtures renders their dereplica-
tion and structural identification difficult using liquid chromatography
coupled to tandem mass spectrometry and efforts are required to improve
the methodology. Researchers developed a supercritical fluid chromato-
graphy (SFC) high-resolution tandem mass spectrometry method, invol-
ving lithium post-column cationisation, for the structural characterisation
of annonaceous acetogenins in crude extracts. They employed supercritical
fluid chromatography using a 2-ethylpyridine stationary phase column,

8
A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 4
Mono-THF α- or α'-monohydroxylated γ-lactone acetogenins (Groups 9).
a b
Hydroxyl positions Relative configuration of THF Molecular formula M+ Species [Ref]

Group 9– THF a-monohydroxylated acetogenins

Group 9a – With OH at C4 (gigantetrocin-A type)

9a.1 gigantetrocin-A 4,14,17,18 t/th-th C35 H64 O7 596 G. giganteus (McLaughlin et al., 1991)
9a.2 densicomacin-1 4,14,17,18 t/er-th C35 H64 O7 596 A. densicoma (Yu et al., 1992)
9a.3 gigantetronenin (Δ21) 4,14,17,18 t/th-th C37 H66 O7 622 G. giganteus (Fang et al., 1992a, 1992b)
9a.4 gigantetrocin-B 4,14,17,18 t/th-th C35 H64 O7 596 A. muricata (Rieser et al., 1993)
9a.5 muricatetrocins-A + B 4,16,19,20 t/er or th-th C35 H64 O7 596 A. muricata (Rieser et al., 1993)
9a.6 senegalene (Δ29) 4,12,13,21 th-t/th C37 H66 O7 622 A. senegalensis (Sahpaz et al., 1994)
9a.7 muricatin-A 4,14,17,18,23 t/th-th C35 H64 O8 612 A. muricata (Li et al., 1994)
(= muricatatin-A) A. muricata (Li et al., 1994)
9a.8 muricatin-B 4,14,17,18,19 t/th-th/er C35 H64 O8 612 A. muricata (Li et al., 1994)
(= muricatatin-B) A. muricata (Li et al., 1994)
9a.9 coriacin (Δ17) 4,14,21,22 t/th-th C37 H66 O7 622 A. coriacea (Meneses Da Silva et al., 1995)
9a.10 murihexocin-A + B 4,7,8,16,19,20 th-t/th-th C35 H64 O9 628 A. muricata (Zeng et al., 1995a, 1995b)
9a.11 muricatalin 4,14,15,17,18 t/er/er-th C35 H64 O8 612 A. muricata (Ghi et al., 1995)
9a.12 annopentocin-A + B 4,10,16,19,20 t/th-th C35 H64 O8 612 A. muricata (Zeng et al., 1996a, 1996b, 1996d)
9a.13 annopentocin-C 4,10,16,19,20 t/th-er C35 H64 O8 612 A. muricata (Zeng et al., 1996a, 1996b, 1996d)
9a.14 4-acetylgigantetrocin-A (OAc-4),14,17,18 t/th-th C37 H66 O8 638 G. giganteus (Zeng et al., 1996a, 1996b, 1996c, 1996d)
9a.15 muricatetrocin-C 4,16,19,20 t/th-er C35 H64 O7 596 R. mucosa (Shi et al., 1996c)
9a.16 glaucafilin 4,16,19,20 t/th-er C35 H64 O7 596 A. glauca (Waechter et al., 1997a, 1997b)
9a.17 glabranin (Δ23) or glaucaflorin 4,16,19,20 t/th-th C37 H66 O7 622 A. glabra (Gallardo et al., 1998a, 1998b)
9a.18 goniotrionin (Δ17) 4,14,16 t/th-ps th C35 H62 O6 578 G. giganteus (Alali et al. 1998a, 1998b)
9a.19 muricoreacin 4,8,10,16,19,20 ps er-t/th-er C35 H64 O9 628 A. muricata (Kim et al., 1998a, 1998b)
9a.20 murihexocin-C 4,7,8,16,19,20 thc-t/th-erc C35 H64 O9 628 A. muricata (Kim et al., 1998a, 1998b)
9a.21 annomolin 4,7,8,18 th-t/th C35 H64 O7 596 A. cherimolia (Kim et al., 2001a, 2001b)
9a.22 muricin-A 4,19,26,27 t/th-th C35 H64 O7 596 A. muricata (Chang and Wu, 2001)
9a.23 muricin-Bd 4,19,26,27 t/th-th C35 H64 O7 596 A. muricata (Chang and Wu, 2001)
9a.24 muricin-C 4,21,24,25 t/th-th C35 H64 O7 596 A. muricata (Chang and Wu, 2001)
9a.25 muricin-D 4,19,22,23 t/th-th C33 H60 O7 568 A. muricata (Chang and Wu, 2001)
9a.26 muricin-E 4,16,22,23 t/th-th C33 H60 O7 568 A. muricata (Chang and Wu, 2001)
9a.27 muricin-F (Δ24) 4,21,27,28 t/th-th C35 H62 O7 594 A. muricata (Chang and Wu, 2001)
9a.28 annocatalin 4,19,28,29 t/th-th C35 H64 O7 596 A. muricata (Liaw et al., 2002)
e
9a.29 monlicin-A 4,7,8,18 t/th-th C35 H64 O7 596 A. montana (Liaw et al., 2005)
e
9a.30 monlicin-B 4,7,8,18 t/th-th C35 H64 O7 596 A. montana (Liaw et al., 2005)
9a.31 squadiolin-C 4,16,21,22 t/th-th C35 H64 O7 596 A. squamosa (Liaw et al., 2008)
9a.32 tucupentol 4,8,16,19,20 t/th-th C35 H64 O8 612 A. montana (Álvarez Colom et al., 2008)
9a.33 annonamuricin-A 4,17,20,21 t/th-er C35 H64 O7 596 A. muricata (Sun et al., 2017)
9a.34 muricin-M 4,19,21,22 t/th-th C35 H64 O7 596 A. muricata (Sun et al., 2016)
9a.35 muricin-L 4,20,23,24 t/th-th C35 H64 O7 596 A. muricata (Sun et al., 2014)
9a.36 muricin-O 4,14,18,19 t/th-th C35 H64 O7 596 A. squamosa (Ma et al., 2019)

Group 9b – Without OH at C4 (gigantriocin type)

9b.1 gigantriocin 14,17,18 t/th-th C35 H64 O6 580 G. giganteus (McLaughlin et al., 1991)
9b.2 gigantrionenin (Δ21) 14,17,18 t/th-th C37 H66 O6 606 G. giganteus (Fang et al., 1992a, 1992b)
9b.3 4-deoxycoriacin (Δ17) 14,21,22 t/th-th C37 H66 O6 606 A. coriacea (Meneses Da Silva et al., 1995)
9b.4 cis-gigantrionenin (Δ21) 14,17,18 c/th-th C37 H66 O6 606 G. giganteus (Zeng et al., 1996a, 1996b, 1996c, 1996d)
9b.5 muricin-H 19,24,25 t/th-th C35 H64 O6 580 A. muricata (Liaw et al., 2002)
9b.6 muricin-I (Δ28) 19,24,25 t/th-th C37 H66 O6 606 A. muricata (Liaw et al., 2002)
9b.7 coriacyclodienin (Δ17; Δ21) 14 t/th C37 H64 O4 572 A. coriacea (Cavé et al. 1997a, 1997b, 1997c)
9b.8 coriacycloenin ((Δ17) 14 t/th C35 H62 O4 546 A. coriacea (Cavé et al. 1997a, 1997b, 1997c)
9b.9 squadiolin-B 16,19,20,23,24 t/th-th-th C37 H68 O8 640 A. squamosa (Liaw et al., 2008)

a
th = threo; er = erythro; t = trans; c = cis.
b
G. = Goniothalamus; A. = Annona; R.. = Rollinia.
c
For 9a.20 the relative configuration is either th-t/th-er or er-t/th-th.
d
9a.23 is the first ACG with the 4S configuration (Mosher method).
e
9a.29 and 9a.30 are diasteroisomers

and it was monitored using a high-resolution quadrupole time-of-flight
mass spectrometer. Lithium iodide was added post-column in the make-up
solvent. For comparison, the same extract was analyzed using high-pres-
sure liquid chromatography coupled to the same mass spectrometer, with
a column based on solid core particles. Sensitivity was similar for both
HPLC and SFC approaches. Retention behaviour and fragmentation
pathways of three different isomer groups are described. The use of SFC-
MS/MS allows the reduction of the time of analysis, of environmental
impact and an increase in the chromatographic resolution, compared to
liquid chromatography (Laboureur et al., 2017).

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 5
Mono-THF acetogenins with a L-B1, L-B2, L-C or L-D lactone moiety (Groups 10 and 11).
a b
Hydroxyl positions Relative configuration of THF Molecular formula M+ Species [Ref]

Group 10 – Mono-THF iso-acetogenins (isoannonacin type)

10.1 isoannonacin 10,15,20 th/t/th C35 H64 O7 596 A. densicoma (Xu et al. 1989a, 1989b)
10.2 isoannonacinone (CO,10) 15,20 th/t/th C35 H62 O7 594 A. densicoma (Xu et al. 1989a, 1989b)
10.3 squamone (CO,9) 15,20 th/t/th C35 H62 O7 594 A. squamosa (Li et al., 1990)
10.4 isoannoreticuin 9,15,20 th/t/th C35 H64 O7 596 A. reticulata (Wu et al., 1992)
10.5 annonacinone-A 10,15,20 th/t/er C35 H64 O7 596 As. triloba (Zhao et al., 1993)
A. muricata (Wu et al., 1995a, 1995b, 1995c,
1995d)
10.6 gigantetrocinone 14,17,18 t/th-th C35 H64 O7 596 As. triloba (Zhao et al., 1993)
10.7 goniothalamicinone 10,13,18 th/t/th C35 H64 O7 596 As. longifolia (Ye et al., 1995)
10.8 murisolinone 15,20 th/t/th C35 H64 O6 580 As. triloba (Chang et al., 1998)
10.9 annomuricinone-D 10,11,15,20 er-th/t/th C35 H64 O8 612 A. muricata (Zeng et al., 1996a, 1996b, 1996d)
10.10 gigantetroneninone (Δ21) 14,17,18 t/th-th C37 H66 O7 622 As. longifolia (Ye et al., 1996a, 1996b, 1996c,
1996d)
10.11 annomontacinone 10,17,22 th/t/th C37 H68 O7 624 G. giganteus (Alali et al., 1997a, 1997b)
10.12 isomurisolenin (Δ11) 15,20 th/t/th C35 H62 O6 578 A. reticulata (Chang et al., 1998)
10.13 mosinone-A (Δ23) (CO,9) 15,20 th/t/th C37 H64 O7 620 A. squamosa (Hopp et al., 1997)
10.14 squamoxinone 11,17,22 th/t/th C37 H68 O7 624 A. squamosa (Hopp et al., 1998a, 1998b)
10.15 xylomaticinone 10,15,20 th/t/th C37 H68 O7 624 G. giganteus (Alali et al., 1999a, 1999b)
10.16 gonioneninone (Δ21) 10,13,18 th/t/th C37 H66 O7 622 G. giganteus (Alali et al. 1998a, 1998b)
10.17 annocherinone (CO,7) 15,20 th/t/th C35 H62 O7 594 A. cherimolia (Woo et al. 1999a, 1999b)
10.18 asitrocinone 12,15,20 er/t/th C35 H64 O7 596 As. triloba (Kim et al., 2000)
10.19 squamoxinone-B 11,17,22 thc/t/erc C37 H68 O7 624 A. squamosa (Hopp et al., 1999)
10.20 squamoxinone-C 11,17,22 thc/t/erc C35 H64 O7 596 A. squamosa (Hopp et al., 1999)
10.21 montanacin-G (CO,10) 8,15,20 th/t/th C35 H62 O8 610 A. montana (Wang et al., 2001)
10.22 montanacin-F 15,20,29 th/t/er C35 H62 O7 594 A. montana (Wang et al., 2002a, 2002b)

Group 11a – Mono-THF b-hydroxy acetogenins (jetein type)

11a.1 jetein 10,15,20 th/t/er C35 H66 O7 598 A. cherimolia (Cortes et al., 1993)

Group 11b – 34- or 36-Hydroxy acetogenins (donnaienin-A type)

11b.1 donnaienin-A + 34-epi 4,15,20,34 th/t/th C35 H64 O7 596 G. donnaiensis (Zhong and De Quan, 1997)
11b.2 donnaienin-B + 34-epi 4,14,17,18,34 t/th-th C35 H64 O8 612 G. donnaiensis (Zhong and De Quan, 1997)
11b.3 goniodonin +34-epi 4,10,15,20,34 th/t/th C35 H64 O8 612 G. donnaiensis (Jiang et al., 1997)
11b.4 cis-goniodonin + 34-epi 4,10,15,20,34 th/c/th C35 H64 O8 612 G. donnaiensis (Jiang et al., 1997)
11b.5 gardnerinin +34-epi 4,10,16,19,20,34 t/th-er C35 H64 O9 628 G. gardneri (Chen et al., 1998a)
11b.6 donnaienin-C + 34-epi (OAc-4),10,15,20,34 th/t/th C37 H66 O9 654 G. donnaiensis (Jiang et al., 1998a, 1998b, 1998c)
11b.7 anmontanin-C (CO,10) 4,17,22,34 th/t/th C35 H62 O8 610 A. montana (Mootoo et al., 2000)
11b.8 montanacin-H + 34-epi (CO,10) 4,8,15,20,34 th/t/er C35 H62 O9 626 A. montana (Wang et al., 2001)
11b.9 montanacin-I + 34-epi 4,15,20,29,34 th/t/th C35 H64 O8 612 A. montana (Wang et al., 2001)
11b.10 montanacin-J + 34-epi 4,15,20,29,34 th/t/er C35 H64 O8 612 A. montana (Wang et al., 2001)
11b.11 parisin 4,15,20,23,24,36 th/t/th-th C37 H68 O9 656 A. salzmani (Queiroz et al., 2003)
11b.12 annomolon-A + 34-epi (CO,11) 15,20,34 th/t/th C35 H62 O7 594 A. cherimolia (Son et al., 2003)
11b.13 annomolon-B + 34-epi (CO,11) 4,15,20,34 th/t/th C35 H62 O8 610 A. cherimolia (Son et al., 2003)

a
th = threo; er = erythro; t = trans.
b
A. = Annona; As. = Asimina; G. = Goniothalamus.
c
10.19 and 10.20: interchangeable relative configuration for the authors.

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 6
Adjacent bis-THF α,α'-dihydroxylated γ-lactone acetogenins (Groups 12–14).
a b
Hydroxyl positions Relative configuration of Molecular formula M+ Species [Ref]
THF

Group 12 – Dihydroxylated acetogenins (uvaricin type)

12.1 uvaricin 15, (OAc-24) th/t/th/t/er C39 H68 O7 648 U. acuminata (Jolad et al., 1982)
12.2 desacetyluvaricin or squamocin-L or neo- 15,24 th/t/th/t/er C37 H66 O6 606 U. acuminata (Jolad et al., 1985; Santos,
desacetyluvaricin 2007; Li et al., 2010)
12.3 neoannonin 13,22 th/t/th/t/er C35 H62 O6 578 A. squamosa (Kawazu et al., 1989)
12.4 isodesacetyluvaricin or squamocin-M 15,24 th/t/th/t/th C37 H66 O6 606 U. narum (Hisham et al., 1991a; Santos,
2007)
12.5 membranacin 15,24 th/c/th/c/er C37 H66 O6 606 R. membranacea (Saez et al., 1993)
12.6 squamocin-I 13,22 er/t/th/t/th C35 H62 O6 578 A. squamosa (Fujimoto et al., 1994)
12.7 squamocin-K 13,22 th/t/th/t/th C35 H62 O6 578 A. squamosa (Fujimoto et al., 1994)
12.8 squamocin-N 15,24 th/c/th/c/th C37 H66 O6 606 A. squamosa (Fujimoto et al., 1994)
12.9 membrarollin 13,22 th/c/th/c/er C35 H62 O6 578 R. membranacea (González et al., 1998)
12.10 annosquacin-A 11,20 th/t/th/t/th C35 H62 O6 578 A. squamosa (Chen et al., 2012)
12.11 annosquacin-B 11,20 th/t/th/t/th C37 H66 O6 606 A. squamosa (Chen et al., 2012)
12.12 annosquacin-D 13,22 th/t/th/t/th C37 H66 O6 606 A. squamosa (Chen et al., 2012)
12.13 folianin-A 12,21 th/t/th/ter C37 H66 O6 606 A. cornifolia (Lima et al., 2010)
12.14 folianin-B 12,21 th/c/th/c/th C37 H66 O6 606 A. cornifolia (Lima et al., 2010)
12.15 joolanin (CO 5) 15,24 th/t/th/ter C37 H64 O7 620 U. chamae (Fall et al., 2006)
12.16 4-desoxylongimicin-B 11,20 th/t/th/t/th C35 H62 O6 578 A. cornifolia (Lima et al., 2010)
12.17 annonareticin 14,23 th/t/th/t/er C37 H66 O7 622 A. squamosa (Li et al., 2010)
12.18 annopurpuricin-C 10,19 er/t/th/t/er C37 H66 O6 606 A. purpurea (Hernández-Fuentes et al.,
2019)
12.19 squamotin-B 8,17 th/t/th/t/er C37 H66 O6 606 A. squamosa (Ma et al., 2019)
12.20 squamotin-C 8,17 th/t/th/t/th C37 H66 O6 606 A. squamosa (Ma et al., 2019)

Group 13 – Trihydroxylated and tetrahydroxylated acetogenins (with OH at C4) (asimicin type)

13.1 asimicin 4,15,24 th/t/th/t/th C37 H66 O7 622 As. triloba (McLaughlin et al., 1986)
13.2 rolliniastatin-1 4,15,24 th/c/th/c/er C37 H66 O7 622 R. mucosa (Pettit et al., 1987)
13.3 rolliniastatin-2 4,15,24 th/t/th/t/er C37 H66 O7 622 R. mucosa (Pettit et al., 1981)
or bullatacin A. bullata (Hui et al., 1989)
13.4 molvizarin 4,13,22 th/t/th/t/er C35 H62 O7 594 A. cherimolia (Cortes et al., 1991a, 1991b,
1991c)
13.5 trilobacin 4,15,24 th/t/er/c/th C37 H66 O7 622 As. triloba (Zhao et al., 1992)
13.6 rioclarin 4,15,24,28 th/t/th/t/er C37 H66 O8 638 R. membranacea (Saez et al., 1993)
13.7 purpureacin-2 4,12,15,24 th/t/th/t/er C37 H66 O8 638 A. purpurea (Cepleanu et al., 1993)
13.8 parviflorin 4,13,22 th/t/th/t/th C35 H62 O7 594 As. parviflora (Anuradha and Prakasa Rao,
1998)
or squamocin-E A. squamosa (Fujimoto et al., 1994)
13.9 annoglaucin 4,10,15,24 th/t/th/t/er C37 H66 O8 638 A. glauca (Etcheverry et al., 1995)
13.10 glaucanisin 4,13,22 th/t/th/t/er C37 H66 O7 622 A. glauca (Waechter et al., 1995)
13.11 30-OH-bullatacin 4,15,24,30 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1995a, 1995b)
13.12 31-OH-bullatacin 4,15,24,31 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1995a, 1995b)
13.13 32-OH-bullatacin 4,15,24,32 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1995a, 1995b)
13.14 araticulin 4,12,15,24 th/t/th/t/th C37 H66 O8 638 A. crassiflora (Santos et al., 1996)
13.15 annonisin 4,8,13,22 th/t/th/t/th C35 H62 O8 610 A. atemoya (Duret et al., 1997a, 1997b)
13.16 10-OH-asimicin 4,10,15,24 th/t/th/t/th C37 H66 O8 638 As. triloba (He et al., 1996)
A. reticulata (Araya et al., 1994a, 1994b)
13.17 10-OH-trilobacin 4,10,15,24 th/t/er/c/th C37 H66 O8 638 As. triloba (He et al., 1996)
13.18 longimicin-A 4,11,20 th/t/th/t/th C37 H66 O7 622 As. longifolia (Ye et al., 1996a, 1996b,
1996c, 1996d)
13.19 longimicin-B 4,11,20 th/t/th/t/th C35 H62 O7 594 As. longifolia (Ye et al., 1996a, 1996b,
1996c, 1996d)
13.20 longimicin-C 4,9,18 th/t/th/t/th C35 H62 O7 594 As. longifolia (Ye et al., 1996a, 1996b,
1996c, 1996d)
13.21 rollimembrin 4,13,22 th/c/th/c/er C35 H62 O7 594 R. membranacea (González et al., 1997)
13.22 glaucanetin 4,13,22 th/t/th/t/th C37 H66 O7 622 A. glauca (Waechter et al., 1997a, 1997b)
13.23 10-OH-glaucanetin 4,10,13,22 th/t/th/t/th C37 H66 O8 638 A. glauca (Waechter et al., 1997a, 1997b)
13.24 purpuracenin 4,10,15,24 th/c/th/c/er C37 H66 O8 638 A. purpurea (Chávez and Mata, 1999)
13.25 27-OH-bullatacin 4,15,24,27 th/t/th/t/er C37 H66 O8 638 A. glabra (Liu et al., 1999a, 1999b)
13.26 atemoyacin-C 4,15,24,28 th/c/th/c/er C35 H62 O8 610 A. atemoya (Wu et al., 1999)
13.27 asimitrin 4,15,24 th/t/th/t/th C37 H66 O8 638 As. triloba (Kim et al., 2005)
13.28 squamocin-1 4,14,23 th/t/th/t/er C37 H66 O7 622 A. squamosa (Miao et al., 2016b)
13.29 4-hydroxy-squamocin Y 4,15,24,28 th/t/th/t/er C37 H66 O8 638 A. squamosa (Li et al., 2017)
13.30 isolongimicin-B 4,11,20 th/t/th/c/er C35 H62 O7 594 A. cornifolia (Lima et al., 2010)
13.31 squamoxinone-E 4,17,26 th/t/th/t/r/er C37 H66 O7 622 A. squamosa (Miao et al., 2016a)
(continued on next page)

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 6 (continued)
a b
Hydroxyl positions Relative configuration of Molecular formula M+ Species [Ref]
THF

13.32 annopurpuricin-D 4,12,21 er/t/th/t/er C37 H66 O7 622 A. purpurea (Hernández-Fuentes et al.,
2019)

Group 14 – Trihydroxylated, dihydroxylated ketonic, tetrahydroxylated and pentahydroxylated acetogenins

Group 14a – Without OH at C4 (squamocin type)
14a.1 squamocin 15,24,28 th/t/th/t/er C37 H66 O7 622 A. squamosa (Fujimoto et al., 1988)
14a.2 isorollinicin 15,24,28 th/t/th/t/er C37 H66 O7 622 R. papilionella (Dabrah and Sneden, 1984a,
1984b)
14a.3 squamocinone (CO,28) 15,24 th/t/th/t/er C37 H64 O7 620 U. narum (Hisham et al., 1991b)
14a.4 motrilin 15,24,29 th/t/th/t/er C37 H66 O7 622 A. cherimolia (Cortes et al. 1991a, 1991b,
1991c)
or annonin-III A. squamosa (Londershausen et al., 1991)
14a.5 squamocin-B 13,22,26 th/t/th/t/er C35 H62 O7 594 A. squamosa (Sahai et al., 1994)
14a.6 squamocin-D 15,24,28 th/t/th/t/th C37 H66 O7 622 A. squamosa (Sahai et al., 1994)
or asiminacin As. triloba (Zhao et al., 1994)
14a.7 squamocin-F 12,15,24 th/t/th/t/th C37 H66 O7 622 A. squamosa (Sahai et al., 1994)
14a.8 asimin 10,15,24 th/t/th/t/th C37 H66 O7 622 As. triloba (Zhao et al., 1994)
14a.9 asiminecin 15,24,29 th/t/th/t/th C37 H66 O7 622 As. triloba (Zhao et al., 1994)
14a.10 bullatin 10,15,24 th/t/th/t/er C37 H66 O7 622 As. triloba (McLaughlin et al., 1994)
14a.11 bullanin 15,24,30 th/t/th/t/er C37 H66 O7 622 As. triloba (McLaughlin et al., 1994)
14a.12 bullacin 6,13,22 th/t/th/t/th C37 H66 O7 594 A. bullata (McLaughlin et al., 1993)
14a.13 trilobin 10,15,24 th/t/er/c/th C37 H66 O7 622 As. triloba (Zhao et al., 1995)
14a.14 asitribin 15,24,28 th/t/er/c/th C37 H66 O7 622 As. triloba (Woo et al. 1995a, 1995b)
14a.15 uleirollin 12,15,24 th/t/th/t/er C37 H66 O7 622 R. ulei (Cavé et al. 1997a, 1997b, 1997c)
14a.16 asiminocin 15,24,30 th/t/th/t/th C37 H66 O7 622 As. triloba (Zhao et al., 1996)
14a.17 bullatetrocin 15,24,31,32 th/t/th/t/er-er C37 H66 O8 638 As. triloba (He et al., 1996)
14a.18 longimicin-D 10,13,22 th/t/th/t/th C37 H66 O7 622 As. longifolia (Ye et al., 1996a, 1996b,
1996c, 1996d)
14a.19 mucoxin 8,14,17 th/t/th/(c)t/th C37 H66 O7 622 R. mucosa (Shi et al., 1996c)
14a.20 rollitacin 15,24,28,29 th/t/th/t/er-er C37 H66 O8 638 R. mucosa (Shi et al., 1997)
(= purpurediolin) A. purpurea (Mata, 1998)
14a.21 guanacone (CO,10) 15,24 th/t/th/t/er C37 H64 O7 620 A. aff. spraguei (Gallardo et al., 1998a,
1998b)
14a.22 spinencin 15,24,28,29 th/t/th/c/er-th C37 H66 O8 638 A. spinescens (Queiroz et al., 1997)
(= uvarigrin) U. grandiflora (Qin et al., 1996)
14a.23 carolin-A 15,24,28 th/t/th/c/er C37 H66 O7 622 A. spinescens (Queiroz et al., 1998)
14a.24 carolin-B 15,24,29 th/t/th/c/er C37 H66 O7 622 A. spinescens (Queiroz et al., 1998)
14a.25 carolin-C 13,22,26 th/t/th/c/er C35 H62 O7 594 A. spinescens (Queiroz et al., 1998)
14a.26 atemotetrolin 15,24,28,29 th/t/th/t/er-th C37 H66 O8 638 A. atemoya (Duret et al., 1998a, 1998b,
1998c)
14a.27 purpurenin 10,15,24,29 th/t/th/t/er C37 H66 O8 638 A. purpurea (Mata, 1998)
14a.28 ophrypetalin 15,24,28 th/c/th/c/er C37 H66 O7 622 O. odoratum (Sung'hwa et al., 1999)
14a.29 salzmanin 12,15,24,28 th/t/er/c/er C37 H66 O8 638 A. salzmanii (Queiroz et al., 1999a, 1999b)
14a.30 rollimusin 10,15,24,28 th/t/th/t/er C37 H66 O8 638 R. mucosa (Liaw et al., 1999a, 1999b)
14a.31 squamocin-O1c 12,15,24,28 th/t/th/t/er C37 H66 O8 638 A. squamosa (Araya et al., 2002)
14a.32 squamocin-O2c 12,15,24,28 th/t/th/t/er C37 H66 O8 638 A. squamosa (Araya et al., 2002)
14a.33 bullacin-B 6,15,24 th/t/th/t/th C37 H66 O7 622 A. squamosa (Hopp et al., 1998a, 1998b)
14a.34 6-OH-desacetyl-uvaricin 6,15,24 th/t/th/t/er C35 H62 O7 594 A. glabra (Liu et al., 2000)
14a.35 6-OH-4-deoxy-squamotacin 6,13,22 th/t/th/t/er C37 H66 O7 622 A. glabra (Liu et al., 2000)
14a.36 microcarpacin-A 15,24,28,33 th/t/th/t/er C37 H66 O8 638 U. microcarpa (Chen et al., 1997)
14a.37 microcarpacin-B (CO,33) 15,24,28 th/t/th/t/er C37 H64 O8 636 U. microcarpa (Tan et al., 1998)
14a.38 salzmanolind 15,17,24,28,29 th/(t)/er-er C37 H66 O9 654 A. salzmanii (Queiroz et al., 2003)
14a.39 15-acetylguanacone (CO,10) (OAc-15),24 th/t/th/t/er C39 H66 O8 662 A. aff. spraguei (Chahboune et al., 2006)
14a.40 24-acetylguanacone (CO,10) 15, (OAc-24) th/t/th/t/er C39 H66 O8 662 A. aff. spraguei (Chahboune et al., 2006)
14a.41 guanaconetin-1 15, (OAc-24,30) th/t/th/t/er C41 H70 O9 706 A. aff. spraguei (Chahboune et al., 2006)
14a.42 guanaconetin-2 24, (OAc-15,30) th/t/th/t/er C41 H70 O9 706 A. aff. spraguei (Chahboune et al., 2006)
14a.43 guanaconetin-3 15, (OAc-24),30 th/t/th/t/er C39 H68 O8 664 A. aff. spraguei (Chahboune et al., 2006)
14a.44 guanaconetin-4 15,24, (OAc-30) th/t/th/t/er C39 H68 O8 664 A. aff. spraguei (Chahboune et al., 2006)
14a.45 atemoyacin-B 13,22,27 th/t/th/t/er C35 H62 O7 594 A. atemoya (Chen et al., 1995)
14a.46 annosquacin-C 11,20,25 th/t/th/t/th C37 H66 O7 622 A. squamosa (Chen et al., 2012)
14a.47 annosquacin-I 10,19,23 th/t/th/t/er C37 H66 O7 622 A. squamosa (Chen et al., 2011)
14a.48 cornifolin 7,17,26 th/t/th/t/er C37 H66 O7 622 A. cornifolia (lima2006)
14a.49 9-OH-folianin 9,12,21 th/t/th/t/er C37 H66 O7 622 A. cornifolia (Alves et al., 2009)
14a.50 squamocin-II 12,21,22 th/t/th/t/er C37 H66 O7 622 A. squamosa (Miao et al., 2016b)
14a.51 squamocin-III 14,23,29 th/t/th/t/er C37 H66 O7 622 A. squamosa (Miao et al., 2016b)
14a.52 28-hydroxy-squamocin-L 15,24,28 th/t/th/t/er C37 H66 O7 622 A. squamosa (Li et al., 2017)
14a.53 squamocin-P 12,14,23,25 th/t/th/t/er C37 H66 O8 638 A. squamosa (Ma et al., 2017)
14a.54 annotacin 8,13,22 th/t/th/c/er C37 H66 O7 622 A. cornifolia (Lima et al., 2010)
14a.55 Squamocin-IV 7,12,21 th/t/th/t/er C37 H66 O7 622 A. squamosa (Miao et al., 2016a)
14a.56 annonfolin 9,11,26 er/t/th/t/th C37 H66 O7 622 A. cornifolia (Lima et al., 2010)
14a.57 squamotin-A 10,17,26 th/t/th/t/er C37 H66 O7 622 A. squamosa (Ma et al., 2019)
14a.58 squamotin-D 12,13,16,25 th/t/th/t/er C37 H66 O8 638 A. squamosa (Ma et al., 2019)

Group 14b – Without OH at C4, but with OH at C5 (panalicin type)

(continued on next page)

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 6 (continued)
a b
Hydroxyl positions Relative configuration of Molecular formula M+ Species [Ref]
THF

14b.1 panalicin 5,15,24,28 th/t/th/t/er C37 H66 O8 638 U. narum (Hisham et al., 1991b)
14b.2 narumicin-I 5,15,24 th/t/th/t/th C37 H66 O7 622 U. narum (Hisham et al., 1991a)
(= uvarigrandin-A) U. grandiflora (Pan and Yu, 1997)
14b.3 narumicin-II 5,15,24 th/t/th/t/er C37 H66 O7 622 U. narum (Hisham et al., 1991a)
14b.4 espelicin 5,15,24,29 th/t/th/t/er C37 H66 O8 638 U. pauci-ovulata (Raynaud et al., 1997)
14b.5 uvariasolin-I 5,6,15,24 th-th/t/th/t/th C37 H66 O8 638 U. pauci-ovulata (Raynaud et al., 1997)
14b.6 uvariasolin-II 5,6,15,24 th-th/t/th/t/er C37 H66 O8 638 U. pauci-ovulata (Raynaud et al., 1997)
14b.7 calamistrin-F 5,17,26 th/t/th/t/th C37 H66 O7 622 U. calamistrata (Zhou et al., 2000)
14b.8 calamistrin-G 5,17,26 th/t/th/t/er C37 H66 O7 622 U. calamistrata (Zhou et al., 2000)

a
th = threo; er = erythro; t = trans; c = cis.
b
U. = Uvaria; A. = Annona; R. = Rollinia; G. = Goniothalamus; As. = Asimina; O. = Ophrypetalum.
c
14a.31 and 14a.32 are C12-epimers for the authors.
d
14a.38: The OH is on the THF ring (at C17).

Elucidation of the relative stereochemistry of the stereogenic cen- chemical shift differences of the carbinolic proton of lactone in the
tres by careful analysis of the 1H and 13C-NMR spectra is now presence of the (R)- and (S)-CSA (Latypov et al., 2002).
straightforward due to possible comparisons of the spectra between Circular dichroism has also been used for the determination of the
those of the natural products and synthetic models. For the determi- absolute configuration of the terminal γ-lactone (Gawronski and Wu,
nation of absolute configurations, the advanced Mosher ester metho- 2010).
dology has allowed several authors to determine unambiguously the
absolute configuration of carbinols present in the vicinity of the THF
4. Types of acetogenins and previously non-described compounds
rings, and thus to assign the whole configuration of the THF units. For
isolated carbinols, the use of 2-NMA (2-napthylmethoxy acetic acid)
Compounds covered in previous review (Bermejo et al., 2005) and
esters is of great interest, since the influence of aromatic rings can ex-
non-described compounds have been included in Tables 1–11 The re-
tend to five carbon–carbon bonds (Duret et al., 1998c).
liable number of reported ACGs should now be considered as 532, 115
Concerning the absolute configuration of the terminal γ-lactone,
of which were not previously described.
several methods have been used and described in the preceding re-
views, but they all required the degradation of natural ACGs in order to
obtain lactic acid derivatives which can be analyzed by chromato- 4.1. Linear ACGs (Group 1)
graphy. Recently, to analyze ACGs by 1H-NMR spectroscopy has been
proposed, in the presence of a chiral solvating agent (CSA), and deduce The isolated natural linear ACGs, claimed as the biogenetic pre-
the absolute configuration of the terminal γ-lactone by analyzing the cursors of epoxy- and THF-ACGs, differed in the degree of unsaturation
and hydroxylation of their alkyl chains. We can consider here four

Table 7
Adjacent bis-THF α-monohydroxylated γ-lactone acetogenins (Group 15).
a b
Hydroxyl positions Relative configuration of THF Molecular formula M+ Species [Ref]

Group 15 – Adjacent bis-THF a-monohydroxylated acetogenins (goniodenin type)

15.1 goniodenin (Δ21) 4,18 t/th/t/th-c C37 H64 O6 604 G. giganteus (Zhang et al., 1995)
15.2 asimilobin 4,18 t/th/t/th C35 H62 O6 578 G. giganteus (Zhang et al., 1995)
As. triloba (Zhao et al., 1993)
15.3 annonsilin-A 20,23,24 t/th/t/th-th C37 H66 O7 622 A. squamosa (Yang et al., 1995)
15.4 rollidecin-A 4,20,23,24 t/th/c/th-th C37 H66 O8 638 R. mucosa (Shi et al., 1996c)
15.5 rollidecin-B 4,20,23,24 t/th/c/th-er C37 H66 O8 638 R. mucosa (Shi et al., 1996c)
15.6 rollinacin 4,10,20 t/th/t/th C35 H62 O7 594 R. mucosa (Shi et al., 1997)
15.7 rollidecin-C 4,20 t/th/c/th C35 H62 O6 578 R. mucosa (Gu et al., 1997)
15.8 rollidecin-D 4,22 t/th/c/th C37 H66 O6 606 R. mucosa (Gu et al., 1997)
15.9 bulladecin 4,20,23,24 t/th/t/th-er C37 H66 O8 638 A. atemoya (Duret et al., 1998a, 1998b, 1998c)
15.10 glabracin-A 4,10,23,24 th/t/th/t-er C37 H66 O8 638 A. glabra (Liu et al., 1998a, 1998b)
15.11 glabracin-B 4,10,23,24 th/t/th/t-th C37 H66 O8 638 A. glabra (Liu et al., 1998a, 1998b)
15.12 annocatacin-A 4,23 t/th/t/th C35 H62 O6 578 A. muricata (Chang et al., 2003)
15.13 annocatacin-B 4,23 c/th/c/th C35 H62 O6 578 A. muricata (Chang et al., 2003)
15.14 atemoyacin-E 4,20,23,26 t/th/t/th C37 H66 O8 638 A. atemoya (Wu et al., 2001)
15.15 robustocin 18 t/th/c/th C35 H62 O5 562 A. muricata (Gleye et al., 2000a, 2000b)
15.16 annopurpuricin-A 6,19,24 t/th/c/th C37 H66 O7 622 A. purpurea (Hernández-Fuentes et al., 2019)
15.17 annopurpuricin-B 4,12,23 er/t/th/t C37 H66 O7 622 A. purpurea (Hernández-Fuentes et al., 2019)

a
th = threo; er = erythro; t = trans; c = cis.
b
G. = Goniothalamus; As. = Asimina; A. = Annona; R. = Rollinia.

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 8
Non-Adjacent bis-THF γ-lactone acetogenins (Groups 16–18).
a b
Hydroxyl positions Relative configuration of THF Molecular formula M+ Species [Ref]

Group 16 – Non-adjacent bis-THF acetogenins (with OH at C4) (sylvaticin type)

16.1 sylvaticin 4,16,19,24 t/th-th/c/er C37 H66 O8 638 R. sylvatica (Mikolajczak et al., 1990)
R. mucosa (Shi et al., 1995a, 1995b)
16.2 gigantecin 4,14,17,22 t/th-th/t/th C37 H66 O8 638 G. giganteus (Bermejo et al., 2005)
16.3 cherimolin-1 4,16,19,24 t/th-th/t/er C37 H66 O8 638 A. cherimolia (Cortes et al., 1993)
or bullatalicin A. bullata (Cortes et al., 1984)
16.4 cherimolin-2 4,16,19,24 t/th-th/t/th C37 H66 O8 638 A. cherimolia (Cortes et al., 1993)
or bullatanocin A. bullata (Gu et al. 1993a, 1993b)
16.5 parvifloracin 4,14,17,22 t/th-th/t/th C35 H62 O8 610 As. parviflora (Ratnayake et al., 1994)
16.6 12,15-cis-bullatalicin 4,16,19,24 c/th-th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1995a, 1995b)
16.7 12,15-cis-bullatanocin 4,16,19,24 c/th-th/t/th C37 H66 O8 638 A. bullata (Gu et al., 1995a, 1995b)
16.8 12,15-cis-sylvaticin 4,16,19,24 c/th-th/c/er C37 H66 O8 638 R. mucosa (Shi et al., 1995a, 1995b)
16.9 trilobalicin 4,14,17,22 t/th-th/t/er C35 H62 O8 610 As. triloba (He et al., 1997a, 1997b)
16.10 goniotriocinc (CO,22) 4,14,18 t/th/c/t C37 H64 O8 636 G. giganteus (Alali et al., 1999a, 1999b)
16.11 annosquatin-II 4, 21,24,29 t/th-th/t/er C37 H66 O8 638 A. squamosa (Chen et al., 2011)
16.12 annosquatin-IV 4,14,17,22 t/th-th/t/er C37 H66 O8 638 A. squamosa (Ma et al., 2019)

Group 17 – Non-adjacent bis-THF acetogenins (without OH at C4) (squamostatin-A or almunequin type)

17.1 squamostatin-A 16,19,24,28 t/th-th/t/er C37 H66 O8 638 A. squamosa (Fujimoto et al., 1990)
or almunequin A. cherimolia (Cortes et al., 1993)
17.2 4-deoxygigantecin 14,17,22 t/th-th/t/th C37 H66 O7 622 G. giganteus (Fang et al., 1992a, 1992b)
17.3 squamostatin-D 16,19,24 t/th-th/t/er C37 H66 O7 622 A. squamosa (Hirayama et al., 1993)
17.4 squamostatin-E 16,19,24 t/th-th/t/th C37 H66 O7 622 A. squamosa (Fujimoto et al., 1994)
17.5 12,15-cis-squamostatin-D 16,19,24 c/th-th/t/er C37 H66 O7 622 A. atemoya (Chang et al., 1999)
17.6 12,15-cis-squamostatin-A 16,19,24,28 c/th-th/t/er C37 H66 O8 638 A. atemoya (Chang et al., 1999)
17.7 annosquatin-A 13,16,21 t/th-th/t/er C37 H66 O7 622 A. squamosa (Chen et al., 2012)
17.8 annosquatin-B 13,16,21,29 t/th-th/t/er C37 H66 O8 638 A. squamosa (Chen et al., 2012)
17.9 annosquatin-I 21,24,29,30 t/th-th/t/er C37 H66 O8 638 A. squamosa (Chen et al., 2011)
17.10 squamostanin-A 15,18,23,27 t/th-th/t/th C37 H66 O8 638 A. squamosa (Yang et al., 2009a)
17.11 squamostanin-B 15,18,23,27 t/th-th/t/er C37 H66 O8 638 A. squamosa (Yang et al., 2009a)
17.12 squamostanin-C 5,16,19,24 t/th-th/t/th C37 H66 O8 638 A. squamosa (Yang et al., 2009b)
17.13 squamostanin-D 5,16,19,24 t/th-th/t/er C37 H66 O8 638 A. squamosa (Yang et al., 2009b)
17.14 squamostatin-C 16,19,24 t/er-th/t/th C37 H66 O8 638 A. squamosa (Li et al., 2010)
17.15 annosquatin-III 12,21,24,29 t/th-th/t/er C37 H66 O8 638 A. squamosa (Ma et al., 2017)
17.16 annosquatin-V 13,16,21 t/th-th/t/th C37 H66 O7 622 A. squamosa (Ma et al., 2019)

Group 18 – 4–7/16–19 Non-adjacent bis-THF acetogenins (aromin type)

18.1 aromin 15,20 t-th/t/th C35 H60 O7 592 X. aromatica (Alfonso et al., 1996)
18.2 aromicin 15,20 t-th/t/th C37 H64 O7 620 X. aromatica (Alfonso et al., 1996)
18.3 aromin-A (CO,9) 15,20 t-thd/t/erd C35 H60 O7 592 A. cherimolia (Chen et al., 1999)

a
th = threo; er = erythro; t = trans; c = cis.
b
R. = Rollinia; G. = Goniothalamus; A. = Annona; As. = Asimina.
c
16.10: The OH is on the THF ring (C18 position).
d
For 18.3 the relative configuration is either th/t/er or er/t/th.

subgroups (1a to 1d) (see Table 1) (Bermejo et al., 2005).
Group 1a – Vicinal dihydroxylated and olefinic acetogenins
(giganin type) They are characterized by the presence of a vicinal diol,
and some of them by one or two double bonds. In all of these ACGs a Z-
geometry for the double bond and a threo relative configuration at the
vicinal diol have been established, except for murihexol (1a.13) which
possesses two vicinal diols containing threo and erythro configurations.
There are two non-described acetogenins (+) -monhexocin (1a.22)
and (−) -monhexocin (1a.23). The only difference between the 1a.22
and 1a.23 isomers is the positive or negative sign of the specific rotation
[α]D (Liaw et al., 2005).
Group 1b – Hydroxylated (or ketonic) linear acetogenins (re-
ticulatamol type) These are characterized by one or more non-vicinal
hydroxyl groups (or a ketone group); only three compounds belong to
this subgroup.
Group 1c – Olefinic and acetylenic acetogenins (muridienin-1
type) There is one non-described acetogenin. Xymarginatin is an ACG
containing an L-A lactone, CO10, two double bonds, and C37 (Colman-
Saizarbitoria et al., 2009).
Group 1d – bis-lactonic linear acetogenins (rollicosin type). Bis-
lactonic linear ACGs are a subgroup of ACGs with one or two hydroxyl
groups, characterized by the presence of two terminal lactone moieties

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Table 9
Satured lactone bis-THF acetogenins (Group 19 and 20).
a b
Hydroxyl positions Relative configuration of THF Molecular formula M+ Species [Ref]

Group 19 – “Iso”-bis-THF acetogenins (bullatacinone type)

19.1 bullatacinone 15,24 th/t/th/t/er C37 H66 O7 622 A. bullata (Hui et al., 1989)
19.2 rollinone 15,24 th/c/th/c/er C37 H66 O7 622 R. papilionella (Dabrah and Sneden, 1984a,
1984b)
19.3 (2,4 cis and trans)bullatalicinonec 16,19,24 th-th/t/er C37 H66 O8 638 A. bullata (Liaw et al., 1999a, 1999b)
or isocherimolin-1 A. cherimolia (Duret et al., 1994)
19.4 bullatanocinone 16,19,24 th-th/t/th C37 H66 O8 638 A. bullata (Gu et al., 1993b)
19.5 bulladecinone 20,23,24 t/th/t/th-er C37 H66 O8 638 A. bullata (Gu et al., 1994a)
19.6 32-OH-bullatacinone 15,24,32 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1993a)
19.7 31-OH-bullatacinone 15,24,31 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1993a)
19.8 30-OH-bullatacinone 15,24,30 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1993a)
19.9 isomolvizarin-1 13,22 th/t/th/t/er C35 H62 O7 594 A. cherimolia (Duret et al., 1994)
19.10 isomolvizarin-2 13,22 th/t/th/t/th C35 H62 O7 594 A. cherimolia (Duret et al., 1994)
19.11 10-OH-bullatacinone 10,15,24 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1994b)
19.12 12-OH-bullatacinone 12,15,24 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1994b)
19.13 29-OH-bullatacinone 15,24,29 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1994b)
19.14 28-OH-bullatacinone 15,24,28 th/t/th/t/er C37 H66 O8 638 A. bullata (Gu et al., 1995a, 1995b)
19.15 (2,4 cis and trans)trilobacinone 15,24 th/t/er/c/th C37 H66 O7 622 As. triloba (He et al., 1997a, 1997b)
19.16 (2,4 cis and trans)gigantecinonec 14,17,22 t/th-th/t/th C37 H66 O8 638 G. giganteus (Alali et al., 1997a, 1997b)
19.17 20,23-cis-bullatalicinonec 16,19,24 t/th-the/c/ere C37 H66 O8 638 R. mucosa (Liaw et al., 1999a, 1999b)
19.18 (2,4 cis and trans)-9-OH-asimicinone 9,15,24 th/t/th/t/th C37 H66 O8 638 A. squamosa (Hopp et al., 1999)
19.19 (2,4 cis and trans)squamolinone 15,24 th/t/th/t/er C35 H62 O7 594 A. squamosa (Hopp et al., 1998a, 1998b)
19.20 (2,4 cis and trans)-9-oxo-asimicinone 15,24 th/t/th/t/th C37 H64 O8 636 A. squamosa (Hopp et al., 1998a, 1998b)
(CO,9)

Group 20 – b-Hydroxy methyl c-lactones (laherradurin type)

20.1 laherradurin 15,24,35 th/t/th/t/er C37 H68 O7 624 A. cherimolia (Ríos et al., 1989)
20.2 itrabin 13,22,33 th/t/th/t/er C35 H64 O7 596 A. cherimolia (Cortes et al. 1991a, 1991b,
1991c)
20.3 otivarin 16,19,24,35 t/th-th/t/er C37 H68 O8 640 A. cherimolia (Cortes et al., 1993)
20.4 tucumanin 15,24,35 th/t/th/t/th C37 H68 O7 624 A. cherimolia (Barrachina et al., 2004)

a
th = threo; er = erythro; t = trans; c = cis.
b
A.. = Annona; R.. = Rollinia; As. = Asimina; G. = Gonothalamus.

Table 10
Tri-tetrahydrofuran acetogenins (Groups 21).
a b
Hydroxyl positions Relative configuration of THF Molecular formula M+ Species [Ref]

Group 21 – Tri-THF acetogenins (goniocin type)

21.1 goniocin 4,22 t/th/t/th/t/th C37 H64 O7 620 G. giganteus (Gu et al., 1994d)

a
b

a
th = threo; t = trans.
b
G. = Goniothalamus.

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 11
Tetrahydropyran acetogenins (Group 22).
a b
Hydroxyl positions Relative configuration of THF Molecular formula M+ Species [Ref]

Group 22a – Mono-THP acetogenins (pyranicin type)

22a.1 pyranicin 4,10,15,19 th-c-t C35 H64 O7 596 G. giganteus (Alali et al. 1998a, 1998b)
22a.2 pyragonicin 4,10,13,17 th-c-t C35 H64 O7 596 G. giganteus (Alali et al. 1998a, 1998b)

Group 22b – Adjacent THF–THP acetogenins (muconin type)

22b.1 muconin 4,12,22 th/c/th/t/th C37 H66 O7 622 R. mucosa (Shi et al., 1996c)
22b.2 jimenezin 4,15,23 th/t/er/c-t C37 H66 O7 622 R. mucosa (Chávez et al., 1998)
22b.3 chamuvarinin 15 nd C37 H64 O6 604 U. chamae (Fall et al., 2004)

Group 22c – Non-adjacent THF–THP acetogenins (mucocin type)

22c.1 mucocin 4,16,19,23 t/th-th/c C37 H66 O8 638 R. mucosa (Shi et al., 1995a, 1995b)
22c.2 montanacin-D (CO,10) 15,20 c-th/t/th C35 H60 O7 592 A. montana (Wang et al., 2000)
22c.3 montanacin-E (CO,10) 15,20 c-th/c/th C35 H60 O7 592 A. montana (Wang et al., 2000)

a
th = threo; er = erythro; t = trans; c = cis; nd = configuration not determined.
b
G. = Goniothalamus; R.. = Rollinia; X. = Xylopia.

on both sides of the aliphatic chain and the lack of either THF or THP
rings (Bermejo et al., 2005).
Group 1e – Olefinic and acetylenic acetogenins (cananginone
type) Twenty compounds with an interesting new type of terminal
lactone, L-E, are described for the first time. Cananginones A-D and G
(1e.1–4 and 1e.7) are ACGs containing an L-E lactone, have a shorter
alkyl chain (C21-24 skeleton) and one or two triple bonds.
Cananginones E, F, H, I (1e.5, 6, 8, 9) are ACGs containing an L-E
lactone, and have a shorter alkyl chain (C21 and 23 skeletons) and one
triple bond and one or two double bonds (Wongsa et al., 2011). Or-
opheolide, 9,10-dihidrooropheolide and mitregenin (1e.18, 16, 17) are
ACGs containing an L-E lactone, double and triple bonds, and have a
shorter alkyl chain (C21 skeleton) (Li et al., 2009; Zhang et al., 2010).
The ACGs debilisone-A-F (1e.10–15) possesses a terminal L-E lactone
and double and triple bonds, containing a C25 and 27 skeletons
(Panthama et al., 2010). Gracilipin-A and methylsaccopetrin-A (1e.19,
20) are ACGs containing an L-E lactone, double and triple bonds, and
have a shorter alkyl chain (C25, 26 skeleton) (Trieu et al., 2018).
4.2. Epoxy-ACGs (Groups 2–4)
In the group of epoxy-ACGs (Table 2), seven compounds, epomur-
inin-A and –B (Melot et al., 2009), neo-epoxyrolin, epoxyrolin-B
(2.7–10), (Li et al., 2010) dieposabadelin, squamocenin-A, dieporeticin,
annopurpuricin-E (3.10–12) (Bajin ba Ndob et al., 2009) and
annopurpuricin-E (3.13) (Hernández-Fuentes et al., 2019), have been
added. As we have demonstrated above, epoxy-ACGs, probably origi-
nating by oxidation of linear and olefinic ACGs, are key metabolites in
the biosynthesis of mono-, bis- and tri-THF ACGs (Bermejo et al., 2005).
4.3. Mono-THF ACGs (Groups 5–11)
Groups 5–8 – Mono-THF-α,α′-dihydroxylated acetogenins
(Table 3). These represent the most important subclass of mono-THF
ACGs, now enlarged by the addition of 6 non-described dihydroxylated
ACGs (type 5) (5.20–25), 6 trihydroxylated and dihydroxylated ketonic
ACGs (type 6) (6.27–32), 15 tetrahydroxylated and trihydroxylated
ketonic ACGs (type 7) (7.a51-58), (7.b14-20) and 5 polyhydroxylated
and tetrahydroxylated ketonic ACGs (type 8) (8.28–31).
A threo–trans–threo or threo–trans–erythro or threo–cis–threo relative
configuration has been established for all the mono-THF-α,α'-dihy-
droxylated ACGs, although there are two compounds with a threo–ci-
s–erythro relative configuration: squafosacin-F and squafosacin-G (5.23
and 5.24) (Liaw et al., 2008). The ACGs dotistenin, lepirenin and
squamocenin-B (5.21, 5.22 and 5.25) differ from the others by the
presence of one double bond. (Bajin ba Ndob et al., 2009; Yu et al.,
2005) as well as the non-described compound squamoxinone-D (6.27)
(Miao et al., 2016b).
Group 9 – Mono-THF-a-monohydroxylated acetogenins
(Table 4). Nine non-described ACGs have been added in this group,

16
A. Neske, et al.
Fig. 2. Tetrahydrofuran (THF), tetrahydropyran (THP), epoxy and γ-lactone systems in ACGs.
which is presented in two subgroups: 4-hydroxylated ACGs (9a.28–31)
annocatalin (Liaw et al., 2002), monlicin-A, monlicin-B (Liaw et al.,
2005), squadiolin-C (Liaw et al., 2008), (9a.32) tucupentol (Álvarez
Colom et al., 2009), (9a.33–36) annonamuricin-A (Sun et al., 2017),
muricin-M (Sun et al., 2016), muricin-L (Sun et al., 2014), muricin-O
(Ma et al., 2019), and one compound without a 4-hydroxyl group (9b.9)
squadiolin-B (Liaw et al., 2008).
The only difference between the 9a.29 and 9a.30 estereoisomers is
the positive or negative sign of the specific rotation [α]D (Liaw et al.,
2005).
Groups 10 and 11 – Mono-THF acetogenins with a L-B1, L-B2, L-
C or L-D lactone moiety (Table 5). The number of “iso”-mono-THF
ACGs (10: isoannonacin type) has not been increased.
4.4. Bis-THF ACGs (Groups 12–20)
New compounds have been included in this group, and these have
been classified into adjacent ACGs (Tables 6 and 7), non-adjacent ACGs
(Table 8) and saturated lactone ACGs (Table 9).
Groups 12–15 – Adjacent bis-THF acetogenins (Tables 6 and 7).
17
Phytochemistry 174 (2020) 112332
Most of the adjacent bis-THF ACGs possesses a bis-THF system flanked
at the α and α' positions by two hydroxyl groups; 25 non-described
compounds have been thus reported (Table 6) (12.10–20), (13.27–32)
and (14a.46–58). Joolanin (12.15) is a previously non-described ACG
with a CO at the C-5 position (Fall et al., 2006). An erythro/trans/threo/
trans/threo relative configuration has been established for annonfolin
(14a.56) (Lima et al., 2010).
Two news adjacent bis-THF monohydroxylated ACGs have been
added (goniodenin type), annopurpuricin-A and annopurpuricin-B
(15.16–17) (Hernández-Fuentes et al., 2019).
Groups 16–18 – Non-adjacent bis-THF acetogenins (Table 8).
Twelve previously non-described compounds have been added to the
group of non-adjacent bis-THF ACGs, two with OH at C4: annosquatin II
and annosquatin-IV (16.11–12) (Chen et al., 2011; Ma et al., 2019), and
ten without OH at C4. Almost all with trans/threo-configuration except
for squamostatin-C (17.14) whose relative configuration has been es-
tablished trans/erythro-threo/trans/threo (Li et al., 2010).
Groups 19 and 20 – Saturated lactone bis-THF acetogenins
(Table 9). There are no described ACGs in the period 2005–2019
(Table 9).
A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 12
Species from the Annonaceae family which have provided new acetogenins.
Species Organ Compounds Ref.

Ampelocissus sp. Roots 6.31 22-epi-calamistrin-B Pettit et al. (2008)

Annona atemoya Mabbmosa) Seed 1a.21 artemoin-A + B + C + D Chang et al. (1999)
(A. cherimolia × A.squamosa) 5.9 annotemoyin-1 Duret et al. (1996)
5.10 annotemoyin-2 Duret et al. (1996)
13.15 annonisin Duret et al. (1997a, 1997b)
14a.26 atemotetrolin Duret et al. (1998a)
14a.45 Atemoyacin-B Chen et al. (1995)
15.9 bulladecin Duret et al. (1998b)
15.14 atemoyacin-E Wu et al. (2001)
17.5 12,15-cis-squamostatin-D Chang et al. (1999)
17.6 12,15-cis-squamostatin-A Chang et al. (1999)
Root 13.26 atemoyacin-C Wu et al. (1999)
Annona bullata A. Rich. Bark 5.5 uvariamicin-IV Hui et al. (1992)
5.6 bullatencin Hui et al. (1992)
13.3 bullatacin (or rolliniastatin-2) Hui et al. (1989)
13.11 30-OH-bullatacin Gu et al. (1995a)
13.12 31-OH-bullatacin Gu et al. (1995a)
13.13 32-OH-bullatacin Gu et al. (1995a)
14a.12 bullacin McLaughlin et al. (1993)
16.3 bullatalicin (or cherimolin-1) Cortes et al. (1984)
16.4 bullatanocin (or cherimolin-2) Gu et al. (1993b)
16.6 12,15-cis-bullatalicin Gu et al. (1995b)
16.7 12,15-cis-bullatanocin Gu et al. (1995b)
19.1 bullatacinone Hui et al. (1989)
19.3 bullatalicinone (or isocherimolin-1) Liaw et al. (1999a)
19.4 bullatanocinone Gu et al. (1993b)
19.5 bulladecinone Gu et al. (1994a)
19.6 32-OH-bullatacinone Gu et al. (1993a)
19.7 31-OH-bullatacinone Gu et al. (1993a)
19.8 30-OH-bullatacinone Gu et al. (1993a)
19.11 10-OH-bullatacinone Gu et al. (1994d)
19.12 12-OH-bullatacinone Gu et al. (1994d)
19.13 29-OH-bullatacinone Gu et al. (1994d)
19.14 28-OH-bullatacinone Gu et al. (1995a)
Annona cherimolia Mill. Seed 7a.36 annocherin Woo et al. (1999a)
7a.40 annocherimolin Kim et al. (2001c)
9a.21 annomolin Kim et al. (2001a)
10.17 annocherinone Woo et al. (1999a)
11a.1 jetein Cortes et al. (1993)
11b.12 annomolon-A + 34-epi Son et al. (2003)
11b.13 annomolon-B + 34-epi Son et al. (2003)
13.4 molvizarin Cortes et al. (1991a)
14a.4 motrilin (or annonin-III) Cortes et al. (1991a)
16.3 cherimolin-1 (or bullatalicin) Cortes et al. (1993)
16.4 cherimolin-2 (or bullatanocin) Cortes et al. (1993)
17.1 almunequin (or squamostatin-A) Cortes et al. (1993)
20.1 laherradurin Ríos et al. (1989)
20.2 itrabin Cortes et al. (1991c)
20.3 otivarin Cortes et al. (1993)
20.4 tucumanin Barrachina et al. (2004)
Stem 18.3 aromin-A Chen et al. (1999)
Root 19.3 isocherimolin-1 (or bullatalicinone) Duret et al. (1994)
19.9 isomolvizarin-1 Duret et al. (1994)
19.10 isomolvizarin-2 Duret et al. (1994)
Annona coriácea Mart. Root 1a.3 coriadienin Meneses da Silva et al. (1996)
8.13 coriheptocin-A Meneses Da Silva et al. (1997)
8.14 coriheptocin-B Meneses Da Silva et al. (1997)
8.23 annoheptocin-A Meneses da Silva et al. (1998)
8.24 annoheptocin-B Meneses da Silva et al. (1998)
9a.9 coriacin Meneses Da Silva et al. (1995)
9b.3 4-deoxycoriacin Meneses Da Silva et al. (1995)
9b.7 coriacyclodienin Cavé et al. (1997b)
9b.8 coriacycloenin Cavé et al. (1997b)
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Table 12 (continued)

Species Organ Compounds Ref.

Annona cornifolia A. St.-Hill Seed 14a.48 cornifolin (lima2006)

14a.49 9-OH-folianin Alves et al. (2009)
12.14 folianin-B Lima et al. (2010)
Annona crassiflora Mart. Seed 13.14 araticulin Santos et al. (1996)
Annona densicoma Mart. Seed 7a.1 annonacin McCloud et al. (1987)
7a.3 annonacinone Xu et al. (1989a)
Bark 8.3 8-OH-annonacin Yu et al. (1992)
9a.2 densicomacin-1 Yu et al. (1992)
10.1 isoannonacin Xu et al. (1989b)
10.2 isoannonacinone Xu et al. (1989b)
Annona glabra L. Seed 9a.17 glabranin Gallardo et al. (1998a)
Leaf 7a.29 glacin-A Liu et al. (1998b)
7a.30 glacin-B Liu et al. (1998b)
7a.34 annoglacin-A Liu et al. (1999a)
7a.35 annoglacin-B Liu et al. (1999a)
8.19 annoglaxin Liu et al. (1999b)
13.25 27-OH-bullatacin Liu et al. (1999b)
14a.34 6-OH-desacetyluvaricin Liu et al. (2000)
14a.35 6-OH,4-deoxysquamotacin Liu et al. (2000)
15.10 glabracin-A Liu et al. (1998a)
15.11 glabracin-B Liu et al. (1998a)
Annona glauca Schumach. & Thomn. Root 13.9 annoglaucin Etcheverry et al. (1995)
Seed 6.19 glaucabellin Waechter et al. (1998)
9a.16 glaucafilin Waechter et al. (1997a)
13.10 glaucanisin Waechter et al. (1995)
13.22 glaucanetin Waechter et al. (1997b)
13.23 10-OH-glaucanetin Waechter et al. (1997b)
Annona jahnii Saff. Twig 1a.14 annojahnin Colman-Saizarbitoria et al. (1998)
1a.16 annodienin Colman-saizarbitoria et al. (1999)
1a.17 jahnonacin Colman-saizarbitoria et al. (1999)
Annona montana Macfad. Seed 6.24 montalicin-A Liaw et al. (2004a)
6.25 montalicin-B Liaw et al. (2004a)
7a.5 annomontacin Jossang et al. (1991)
7a.44 montalicin-C Liaw et al. (2004a)
7a.45 montalicin-D Liaw et al. (2004a)
7a.46 cis-annoreticuin Liaw et al. (2004a)
7a.47 montalicin-E Liaw et al. (2004a)
7a.48 montalicin-F Liaw et al. (2004a)
7a.49 montalicin-I Liaw et al. (2004a)
7a.50 montalicin-J Liaw et al. (2004a)
8.1 annomonicin Jossang et al. (1990)
8.2 montanacin Jossang et al. (1990)
8.26 montacin Liaw et al. (2004b)
8.27 cis-montacin Liaw et al. (2004b)
1a.22 (+)-monhexocin Liaw et al. (2005)
1a.23 (−)-monhexocin Liaw et al. (2005)
9a.29 monlicin-A Liaw et al. (2005)
9a.30 monlicin-B Liaw et al. (2005)
8.28 montanlicin-G Liaw et al. (2005)
8.29 montalicin-H Liaw et al. (2005)
Fruit 3.6 diepoxymontin Wu et al. (1994)
Leaf 7a.37 anmontanin-A Mootoo et al. (2000)
8.20 anmontanin-B Mootoo et al. (2000)
8.21 montanacin-B Wang et al. (2000)
8.22 montanacin-C Wang et al. (2000)
10.21 montanacin-G Wang et al. (2001)
10.22 montanacin-F Wang et al. (2002a)
11b.7 anmontanin-C Mootoo et al. (2000)
11b.8 montanacin-H + 34-epi Wang et al. (2001)
11b.9 montanacin-I + 34-epi Wang et al. (2001)
11b.10 montanacin-J + 34-epi Wang et al. (2001)
22c.2 montanacin-D Wang et al. (2000)
22c.3 montanacin-E Wang et al. (2000)
Leaf and 9a.32 tucupentol Álvarez Colom et al. (2009)
twig
(continued on next page)

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 12 (continued)

Species Organ Compounds Ref.

Annona muricata L. Seed 1a.13 murihexol Yu et al. (1998)

1a.15 cohibin-C + D Gleye et al. (2000b)
1a.18 muricatenol De Yu et al. (2000)
2.1 epomuricenin-A (or epoxymurin-A) Roblot et al. (1993)
2.3 epomuricenin-B Roblot et al. (1993)
3.1 diepomuricanin-A Laprévote et al. (1992)
3.2 corepoxylone Gromek et al. (1993)
5.4 solamin Myint et al. (1991)
5.17 15-palmitoylsolamin Gleye et al. (1998b)
5.18 15-oleylsolamin Gleye et al. (1998b)
6.1 murisolin Myint et al. (1990)
6.2 corossolin Cortes et al. (1991b)
6.3 corossolone Cortes et al. (1991b)
7a.19 cis-annonacin Rieser et al. (1996)
7a.20 cis-annonacinone Rieser et al. (1996)
7a.21 cis-goniothalamicin Rieser et al. (1996)
7a.22 arianacin + javoricin Rieser et al. (1996)
7a.39 cis-annomontacin Liaw et al. (2004b)
7a.42 muricin-G Kim et al. (2001b)
8.12 muricatalicin Gui and Yu (1996)
8.25 muricatatin-C Li et al. (1994)
9a.4 gigantetrocin-B Rieser et al. (1993)
9a.5 muricatetrocin-A + B Rieser et al. (1993)
9a.11 muricatalin Ghi et al. (1995)
9a.22 muricin-A Chang and Wu (2001)
9a.23 muricin-B Chang and Wu (2001)
9a.24 muricin-C Chang and Wu (2001)
9a.25 muricin-D Chang and Wu (2001)
9a.26 muricin-E Chang and Wu (2001)
9a.27 muricin-F Chang and Wu (2001)
9b.5 muricin-H Liaw et al. (2002)
9b.6 muricin-I Liaw et al. (2002)
15.12 annocatacin-A Chang et al. (2003)
15.13 annocatacin-B Chang et al. (2003)
15.15 robustocin Gleye et al. (2000a)
Bark 2.1 epoxymurin-A (or epomuricenin-A) Hisham et al. (1993)
2.2 epoxymurin-B Hisham et al. (1993)
8.6 muricatin-C Li et al. (1994)
9a.7 muricatin-A Li et al. (1994)
9a.8 muricatin-B Li et al. (1994)
Leaf 7a.18 annomutacin Wu et al. (1995d)
8.4 annomuricin-A Wu et al. (1995a)
8.5 annomuricin-B Wu et al. (1995a)
8.7 muricatocin-A Wu et al. (1995b)
8.8 muricatocin-B Wu et al. (1995b)
8.9 muricatocin-C Wu et al. (1995c)
8.10 annomuricin-C Wu et al. (1995c)
8.11 annohexocin Zeng et al. (1995b)
8.16 annomuricin-E Kim et al. (1998a, 1998b)
8.17 muricapentocin Kim et al. (1998a, 1998b)
9a.10 murihexocin-A + B Zeng et al. (1995a)
9a.12 annopentocin-A + B Zeng et al. (1996a, 1996b, 1996d)
9a.13 annopentocin-C Zeng et al. (1996a, 1996b, 1996d)
9a.19 muricoreacin Kim et al. (1998a, 1998b)
9a.20 murihexocin-C Kim et al. (1998a, 1998b)
10.9 annomuricinone-D Zeng et al. (1996a, 1996b, 1996d)
Root 1a.5 montecristin Gleye et al. (1997a)
1a.6 cohibin-A Gleye et al. (1997b)
1a.7 cohibin-B Gleye et al. (1997b)
1c.1 muridienin-1 Gleye et al. (1996)
1c.2 muridienin-2 Gleye et al. (1996)
1c.5 chatenaytrienin-1 + 2 Gleye et al. (1998a)
1c.6 chatenaytrienin-3 + 4 Gleye et al. (1998a)
1c.7 muricadienin Gleye et al. (1998a)
1c.8 muridienin-3 + 4 Gleye et al. (1998a)
2.6 sabadelin Gleye et al. (1999)
3.9 coronin Gleye et al. (2001)
5.11 cis-solamin Gleye et al. (1998a)
5.12 cis-panatellin Gleye et al. (1998a)
5.13 cis-uvariamicin-IV Gleye et al. (1998a)
5.14 cis-uvariamicin-I Gleye et al. (1998a)
5.15 cis-reticulatacin Gleye et al. (1998a)
6.16 cis-reticulatacin-10-one Gleye et al. (1998a)
Ripe fruit 2.7 epomurinin-A Melot et al. (2009)
2.8 epomurinin-B Melot et al. (2009)
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Table 12 (continued)

Species Organ Compounds Ref.

Annona nutans R. E. Fr. Root 1a.15 cohibin-C + D Gleye et al. (2000b)

1c.5 chatenaytrienin-1 + 2 Gleye et al. (1998c)
1c.6 chatenaytrienin-3 + 4 Gleye et al. (1998c)
1c.7 muricadienin Gleye et al. (1998c)
1c.8 muridienin-3 + 4 Gleye et al. (1998c)
Annona purpurea Moc. & Sessé ex Dunal. Leaf 13.7 purpureacin-2 Cepleanu et al. (1993)
Seed 13.24 purpuracenin Chávez and Mata (1999)
14a.27 purpurenin Mata (1998)
Root 15.16 annopurpuricin-A Hernández-Fuentes et al. (2019)
15.17 annopurpuricin-B Hernández-Fuentes et al. (2019)
12.18 annopurpuricin-C Hernández-Fuentes et al. (2019)
13.32 annopurpuricin-D Hernández-Fuentes et al. (2019)
3.13 annopurpuricin-E Hernández-Fuentes et al. (2019)
Annona reticulata L. Bark 5.2 reticulatacin (or uvariamicin-II) Saad et al. (1991)
7a.11 reticulacinone Hisham et al. (1994)
Leaf 7a.6 annoreticuin Wu et al. (1992)
7a.7 annoreticuinone Chan et al. (1993)
10.4 isoannoreticuin Wu et al. (1992)
Seed 1b.1 reticulatamol Thi Tam et al. (1994)
1b.2 reticulatamone Tam et al. (1995)
3.3 dieporeticanin-1 Tam et al. (1994)
3.4 dieporeticanin-2 Tam et al. (1994)
3.5 dieporeticenin Tam et al. (1994)
5.7 reticulatain-1 Tam et al. (1995)
5.8 reticulatain-2 Tam et al. (1995)
10.12 isomurisolenin Chang et al. (1998)
Annona salzmannii A. DC. Root 11b.11 parisin Queiroz et al. (2003)
14a.29 salzmanin Queiroz et al. (1999b)
14a.38 salzmanolin Queiroz et al. (2003)
Annona senegalensis Pers. Seed 7a.15 annogalene (or xylomatenin) Sahpaz et al. (1996)
7a.16 annosenegalin Sahpaz et al. (1996)
9a.6 senegalene Sahpaz et al. (1994)
Annona spinescens Mart. Seed 8.18 araticin Queiroz et al. (1999a)
14a.22 spinencin Queiroz et al. (1997)
14a.23 carolin-A Queiroz et al. (1998)
14a.24 carolin-B Queiroz et al. (1998)
14a.25 carolin-C Queiroz et al. (1998)
Annona spraguei Saff. Seed 14a.21 guanacone Gallardo et al. (1998b)
14a.39 15-acetylguanacone Chahboune et al. (2006)
14a.40 24-acetylguanacone Chahboune et al. (2006)
14a.41 guanaconetin-1 Chahboune et al. (2006)
14a.42 guanaconetin-2 Chahboune et al. (2006)
14a.43 guanaconetin-3 Chahboune et al. (2006)
14a.44 guanaconetin-4 Chahboune et al. (2006)
(continued on next page)

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Table 12 (continued)

Species Organ Compounds Ref.

Annona squamosa L. Seed 1d.2 squamostolide Xie et al. (2003)

7a.4 annonacin-A Lieb et al. (1990)
7a.12 squamosten-A Araya et al. (1994a, 1994b)
7a.27 mosin-B Hopp et al. (1997)
7a.28 mosin-C Hopp et al. (1997)
10.13 mosinone-A Hopp et al. (1997)
10.19 squamoxinone-B Hopp et al. (1999)
10.20 squamoxinone-C Hopp et al. (1999)
12.3 neoannonin Kawazu et al. (1989)
12.6 squamocin-I Fujimoto et al. (1994)
12.7 squamocin-K Fujimoto et al. (1994)
12.8 squamocin-N Fujimoto et al. (1994)
13.8 squamocin-E (or parviflorin) Fujimoto et al. (1994)
14a.1 squamocin Fujimoto et al. (1988)
14a.4 annonin-III (or motrilin) Londershausen et al. (1991)
14a.5 squamocin-B Sahai et al. (1994)
14a.6 squamocin-D (or asiminacin) Sahai et al. (1994)
14a.7 squamocin-F Sahai et al. (1994)
14a.31 squamocin-O1 Araya et al. (2002)
14a.32 squamocin-O2 Araya et al. (2002)
15.3 annonsilin-A Yang et al. (1995)
17.1 squamostatin-A (or almunequin) Fujimoto et al. (1990)
17.3 squamostatin-D Hirayama et al. (1993)
17.4 squamostatin-E Fujimoto et al. (1994)
3.10 dieposabadelin Bajin ba Ndob et al. (2009)
3.11 squamocenin-A Bajin ba Ndob et al. (2009)
5.25 squamocenin-B Yu et al. (2005)
8.31 squadiolin-A Liaw et al. (2008)
9b.9 squadiolin-B Liaw et al. (2008)
9a.31 squadiolin-C Liaw et al. (2008)
7b.20 squafosacin-B Liaw et al. (2008)
6.30 squafosacin-C Liaw et al. (2008)
5.23 squafosacin-F Liaw et al. (2008)
5.24 squafosacin-G Liaw et al. (2008)
12.10 annosquacin-A Chen et al. (2012)
12.11 annosquacin-B Chen et al. (2012)
14a.46 annosquacin-C Chen et al. (2012)
12.12 annosquacin-D Chen et al. (2012)
14a.47 annosquacin-I Chen et al. (2011)
17.7 annosquatin-A Chen et al. (2012)
17.8 annosquatin-B Chen et al. (2012)
17.9 annosquatin-I Chen et al. (2011)
16.11 annosquatin-II Chen et al. (2011)
17.10 squamostanin-A Yang et al. (2009a, 2009b, 2009c)
17.11 squamostanin-B Yang et al. (2009a, 2009b, 2009c)
17.12 squamostanin-C Yang et al. (2009a, 2009b, 2009c)
17.13 squamostanin-D Yang et al. (2009a, 2009b, 2009c)
14a.57 squamotin-A Ma et al. (2019)
12.19 squamotin-B Ma et al. (2019)
12.20 squamotin-C Ma et al. (2019)
14a.58 squamotin-D Ma et al. (2019)
16.12 annosquatin-IV Ma et al. (2019)
17.16 annosquatin-V Ma et al. (2019)
9a.36 muricin-O Ma et al. (2019)
7a.58 squamosten-B Ma et al. (2019)
Bark 6.14 4-deoxyannoreticuin Hopp et al. (1998a)
6.15 cis-4-deoxyannoreticuin Hopp et al. (1998a)
10.3 squamone Li et al. (1990)
10.14 squamoxinone Hopp et al. (1998a)
14a.33 bullacin-B Hopp et al. (1998b)
19.18 9-OH-asimicinone Hopp et al. (1999)
19.19 squamolinone Hopp et al. (1998b)
Artabotrys hexapetalus (L.f.) Bhandari Aerial parts 19.20 9-oxo-asimicinone Hopp et al. (1998b)
1c.12 artapetalin-A Wong and Brown (2002)
1c.13 artapetalin-B Wong and Brown (2002)
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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 12 (continued)

Species Organ Compounds Ref.

Asimina longifolia Kral Leaf; twig 1c.14 artapetalin-C Wong and Brown (2002)
1b.3 longanin Ye et al. (1996a)
6.11 longifolicin Ye et al. (1996a)
6.12 longicoricin Ye et al. (1996a)
7a.17 longicin Ye et al. (1995)
7a.24 4-acetylannonacin Ye et al. (1996b)
7a.25 4-acetylxylomaticin Ye et al. (1996b)
10.7 goniothalamicinone Ye et al. (1995)
10.10 gigantetroneninone Ye et al. (1996a)
13.18 longimicin-A Ye et al. (1996b)
13.19 longimicin-B Ye et al. (1996b)
13.20 longimicin-C Ye et al. (1996b)
Asimina parviflora (Michx.) Dunal Stem 14a.18 longimicin-D Ye et al. (1996b)
13.8 parviflorin (or squamocin-E) Anuradha and Prakasa Rao (1998)
16.5 parvifloracin Ratnayake et al. (1994)
Asimina triloba (L.) Dunal Roots and 13.1 asimicin McLaughlin et al. (1986)
seed
husks 10.5 annonacinone-A Zhao et al. (1993)
10.6 gigantetrocinone Zhao et al. (1993)
13.5 trilobacin Zhao et al. (1992)
13.16 10-OH-asimicin He et al. (1996)
13.17 10-OH-trilobacin He et al. (1996)
14a.6 asiminacin (or squamocin-D) Zhao et al. (1994)
14a.8 asimin Zhao et al. (1994)
14a.9 asiminecin Zhao et al. (1994)
14a.10 bullatin McLaughlin et al. (1994)
14a.11 bullanin McLaughlin et al. (1994)
14a.16 asiminocin Zhao et al. (1996)
14a.17 bullatetrocin He et al. (1996)
16.9 trilobalicin He et al. (1997a)
19.15 trilobacinone He et al. (1997b)
Seed 6.5 asiminenin-A Woo et al. (1995a)
6.6 asiminenin-B Woo et al. (1995a)
6.7 cis-murisolin Woo et al. (1995b)
6.8 murisolin-A Woo et al. (1995b)
7a.32 asitrilobin-A Woo et al. (1999b)
7a.33 asitrilobin-B Woo et al. (1999b)
7a.41 asitrocin Kim et al. (2000)
7a.43 asitrilobin-C Woo et al. (2000)
7b.12 asitrilobin-D Woo et al. (2000)
10.8 murisolinone Chang et al. (1998)
10.18 asitrocinone Kim et al. (2000)
14a.13 trilobin Zhao et al. (1995)
14a.14 asitribin Woo et al. (1995a)
15.2 asimilobin Zhao et al. (1993)
13.27 asimitrin Kim et al. (2005)
Cananga latifolia (Hook. f. & Thomson) Finet & stem bark 1c.15 cananginone-A Wongsa et al. (2011)
Gagnep 1c.16 cananginone-B Wongsa et al. (2011)
1c.17 cananginone-C Wongsa et al. (2011)
1c.18 cananginone-D Wongsa et al. (2011)
1c.19 cananginone-E Wongsa et al. (2011)
1c.20 cananginone-F Wongsa et al. (2011)
1c.21 cananginone-G Wongsa et al. (2011)
1c.22 cananginone-H Wongsa et al. (2011)
1c.23 cananginone-I Wongsa et al. (2011)
Dasymaschalon sootepense Craib Leaf 7b.10 sootepensin-A Sinz et al. (1998)
7b.11 sootepensin-B Sinz et al. (1998)
Disepalum anomalum Hook. f. Bark 7a.26 disepalin Ee et al. (1996)
Disepalum plagioneurum (Diels) D. M. Johnson leaves 7b.15 plagioneurin-A Éparvier et al. (2006)
7b.16 plagioneurin-B Éparvier et al. (2006)
7b.17 plagioneurin-C (CO,10) Éparvier et al. (2006)
7b.18 plagioneurin-D (CO,10) Éparvier et al. (2006)
7b.19 plagioneurin-E (CO,10) Éparvier et al. (2006)
6.29 plagionicin-B (CO,10) Éparvier et al. (2006)
8.30 plagionicin-C Éparvier et al. (2006)
7b.14 plagionicin-D (CO,5) Éparvier et al. (2006)
Goniothalamus amuyon (Blanco) Merr. Seed known acetogenins (6.2, 7a.1 and 9a.1) Cortes et al. (1991b, McLaughlin et al. (1991) and
McCloud et al. (1987)
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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 12 (continued)

Species Organ Compounds Ref.

Goniothalamus donnaiensis Finet & Gagnep. Root 1a.11 donhexocin Jiang et al. (1998c)
1a.12 donbutocin Jiang et al. (1998c)
1a.19 donhepocin +34-epi Jiang et al. (1998c)
1a.20 donnaienin-D + 34-epi Jiang et al. (1998a, 1998b, 1998c)
8.15 donnaienin Jiang et al. (1998a, 1998b, 1998c)
11b.1 donnaienin-A + 34-epi Zhong and De Quan (1997)
11b.2 donnaienin-B + 34-epi Zhong and De Quan (1997)
11b.3 goniodonin +34-epi Jiang et al. (1997)
11b.4 cis-goniodonin + 34-epi Jiang et al. (1997)
11b.6 donnaienin-C + 34-epi Jiang et al. (1998a, 1998b, 1998c)
Goniothalamus gardneri Hook. f. & Thomson Root 1a.9 gardnerilin-A Chen et al. (1998b)
1a.10 gardnerilin-B Chen et al. (1998b)
11b.5 gardnerinin +34-epi Chen et al. (1998a)
Aerial parts 1c.9 goniothalamusin Seidel et al. (1999)
Goniothalamus giganteus Hook. f. & Thomson Bark 1a.1 giganin Fang et al. (1993)
6.4 giganenin McLaughlin et al. (1992)
6.13 4-deoxyannomontacin Alali et al. (1997a)
7a.2 goniothalamicin Seidel et al. (1999)
7a.13 gonionenin Gu et al. (1994c)
7a.31 goniotetracin Alali et al. (1998b)
7b.8 gigantransenin-A + B Zeng et al. (1996c)
7b.9 gigantransenin-C Zeng et al. (1996c)
9a.1 gigantetrocin-A McLaughlin et al. (1991)
9a.3 gigantetronenin Fang et al. (1992a)
9a.14 4-acetylgigantetrocin-A Zeng et al. (1996a, 1996b, 1996d)
9a.18 goniotrionin Alali et al. (1998a)
9b.1 gigantriocin McLaughlin et al. (1991)
9b.2 gigantrionenin Fang et al. (1992a)
9b.4 cis-gigantrionenin Zeng et al. (1996a, 1996b, 1996d)
10.11 annomontacinone Alali et al. (1997a)
10.15 xylomaticinone Alali et al. (1999a, 1999b)
10.16 gonioneninone Alali et al. (1998b)
15.1 goniodenin Zhang et al. (1995)
15.2 asimilobin Zhang et al. (1995)
16.2 gigantecin Alkofahi et al. (1990)
16.10 goniotriocin Alali et al. (1999a, 1999b)
17.2 4-deoxygigantecin Fang et al. (1992b)
19.16 gigantecinone Alali et al. (1997b)
21.1 goniocin Gu et al. (1994b)
22a.1 pyranicin Alali et al. (1998a)
22a.2 pyragonicin Alali et al. (1998a)
Goniothalamus sesquipedalis (Wall.) Hook. f. & Thomson Bark known acetogenin (9a.1)
Mitrephora glabra Scheff. Stem bark 1c.30 9,10- dihydrooropheolide Li et al. (2009)
1c.32 oropheolide Li et al. (2009)
Mitrephora maingayi Hook. f. & Thomson 1c.31 mitregenin Zhang et al. (2010)
Ophrypetalum odoratum Diels Leaf 14a.28 ophrypetalin Sung'hwa et al. (1999)
Polyalthia debilis Finet & Gagnep. root 1c.24 debilisone-A Panthama et al. (2010)
1c.25 debilisone-B Panthama et al. (2010)
1c.26 debilisone-C Panthama et al. (2010)
1c.27 debilisone-D Panthama et al. (2010)
1c.28 debilisone-E Panthama et al. (2010)
1c.29 debilisone-F Panthama et al. (2010)
Polyalthia plagioneura Diels Seed 7b.1 plagionicin-A Zheng et al. (1994)
Porcelia macrocarpa R. E. Fr. Seed 1c.3 butyrolactone-1 Chaves and Roque (1997)
1c.4 butyrolactone-2 Chaves and Roque (1997)
Rollinia laurifolia Schltdl. Leaf 5.16 laurifolin Santos Pimenta et al. (2001)
Rollinia membranácea Planch. & Triana Seed 3.7 diepomuricanin-B Sahpaz et al. (1997)
3.8 diepoxyrollin Sahpaz et al. (1997)
4.1 tripoxyrollin Sahpaz et al. (1993)
12.5 membranacin Saez et al. (1993)
12.9 membrarollin González et al. (1998)
13.6 rioclarin Saez et al. (1993)
13.21 rollimembrin González et al. (1997)
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Table 12 (continued)

Species Organ Compounds Ref.

Rollinia mucosa (Jacq.) Baill. Seed 13.2 rolliniastatin-1 Pettit et al. (1987)
13.3 rolliniastatin-2 Pettit et al. (1981)
22b.2 jimenezin Chávez et al. (1998)
Leaf 7a.23 rollinecin-A + B Shi et al. (1996c)
9a.15 muricatetrocin-C Shi et al. (1996a)
14a.19 mucoxin Shi et al. (1996b)
14a.20 rollitacin Shi et al. (1997)
15.4 rollidecin-A Shi et al. (1996a)
15.5 rollidecin-B Shi et al. (1996a)
15.6 rollinacin Shi et al. (1997)
15.7 rollidecin-C Gu et al. (1997)
15.8 rollidecin-D Gu et al. (1997)
16.8 12,15-cis-sylvaticin Shi et al. (1995b)
22c.1 mucocin Shi et al. (1995a)
22b.1 muconin Shi et al. (1996b)
Fruit 1d.1 rollicosin Liaw et al. (2003)
2.4 epomusenin-A Chen et al. (1996a)
2.5 epomusenin-B Chen et al. (1996a)
7a.38 rolliacocin Liaw et al. (1999a)
14a.30 rollimusin Liaw et al. (1999b)
Rollinia papilionella Diels Root 14a.2 isorollinicin Dabrah and Sneden (1984a)
19.2 rollinone Dabrah and Sneden (1984b)
Rollinia serícea R. E. Fr. Bark known acetogenins (13.2 and 14a.1)
Rollinia sylvatica (A. St. –Hill.) Martius Fruit 16.1 sylvaticin Mikolajczak et al. (1990)
Rollinia ulei Diels Leaf 14a.15 uleirollin Cavé et al. (1997a)
Saccopetalum prolificum (Chun & F. C. How) Tsiang Root 1c.10 saccopetrin-A Wang et al. (2002b)
1c.11 saccopetrin-B Wang et al. (2002b)
Uvaria acuminata Oliv. Root 12.1 uvaricin Jolad et al. (1982)
12.2 desacetyluvaricin Jolad et al. (1985)
Uvaria boniana Finet & Gagnep. Bark 6.26 uvaribonianin Qin et al. (1996)
7b.13 uvaribonin Qin et al. (1996)
Uvaria calamistrata Hance Root 6.17 calamistrin-A Zhou et al. (1999)
6.18 calamistrin-B Zhou et al. (1999)
6.21 calamistrin-C Zhou et al. (2000)
6.22 calamistrin-D Zhou et al. (2000)
6.23 calamistrin-E Zhou et al. (2000)
14b.7 calamistrin-F Zhou et al. (2000)
14b.8 calamistrin-G Zhou et al. (2000)
Uvaria chamae P. Beauv. Root 5.19 cis-bullatencin Fall et al. (2002)
22b.3 chamuvarinin Fall et al. (2004)
seed 12.15 joolanin Fall et al. (2006)
Uvaria grandiflora Roxb. Ex Hornem. Root 6.9 uvarigranin Pan and Yu (1995)
6.20 uvarigrin Pan and Yu (1997)
Uvaria microcarpa Champ. Ex Benth Seed 14a.36 microcarpacin-A Chen et al. (1997)
14a.37 microcarpacin-B Tan et al. (1998)
Uvaria narum A. DC. Root 5.1 uvariamicin-I Hisham et al. (1990)
5.2 uvariamicin-II (or reticulatacin) Hisham et al. (1990)
5.3 uvariamicin-III Hisham et al. (1990)
12.4 isodesacetyluvaricin Hisham et al. (1991a)
14.3 squamocinone Hisham et al. (1991a)
14b.1 panalicin Hisham et al. (1991a)
14b.2 narumicin-I Hisham et al. (1991b)
14b.3 narumicin-II Hisham et al. (1991b)
Uvaria pauci-ovulata Hook. f. & Thomson Root 14b.4 espelicin Raynaud et al. (1997)
14b.5 uvariasolin-I Raynaud et al. (1997)
14b.6 uvariasolin-II Raynaud et al. (1997)
Uvaria tonkinensis Finet & Gagnep. Root 1a.4 tonkinelin Chen and Yu (1996a)
6.10 tonkinecin Chen and Yu (1996b)
7b.2 tonkinin-A Chen et al. (1996b)
7b.3 tonkinin-B Chen et al. (1996b)
7b.4 tonkinin-C Chen et al. (1996b)
7b.5 tonkinesin-A Chen et al. (1996b)
7b.6 tonkinesin-B Chen et al. (1996b)
7b.7 tonkinesin-C Chen et al. (1996b)
Xylopia aromatica (Lam.) Mart. Bark 1a.2 venezenin Colman-Saizarbitoria et al. (1995)
1a.8 venezinone Colman-Saizarbitoria et al. (1996)
7a.8 xylopianin Colman-Saizarbitoria et al. (1994b)
7a.9 xylopiacin Colman-Saizarbitoria et al. (1994b)
7a.10 xylomaticin Colman-Saizarbitoria et al. (1994b)
7a.14 xylopien Colman-Saizarbitoria et al. (1994a)
7a.15 xylomatenin (or annogalene) Colman-Saizarbitoria et al. (1994a)
18.1 aromin Alfonso et al. (1996)
18.2 aromicin Alfonso et al. (1996)
Xylopia emarginata Mart. twigs 1c.35 Xymarginatin Colman-Saizarbitoria et al. (2009)

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Table 13 Table 13 (continued)

Names of acetogenins from Annonaceae cited in this review (in al-
phabetic order). 7a.18 annomutacin
7a.1 annonacin
1a.23 (−)-monhexocin 7a.4 annonacin-A
1a.22 (+)-monhexocin 7a.3 annonacinone
13.16 10-hydroxy-asimicin 10.5 annonacinone-A
19.11 10-hydroxy-bullatacinone 9a.33 annonamuricin-A
13.23 10-hydroxy-glaucanetin 7a.51 annonamuricin-B
13.17 10-hydroxy-trilobacin 7a.52 annonamuricin-C
16.6 12,15-cis-bullatalicin 7a.53 annonamuricin-D
16.7 12,15-cis-bullatanocin 12.17 annonareticin
17.6 12,15-cis-squamostatin-A 14a.56 annonfolin
17.5 12,15-cis-squamostatin-D 14a.4 annonin-III (or motrilin)
16.8 12,15-cis-sylvaticin 13.15 annonisin
19.12 12-hydroxy-bullatacinone 15.3 annonsilin-A
14a.39 15-acetylguanacone 9a.12 annopentocin-A + B
5.18 15-oleylsolamin 9a.13 annopentocin-C
5.17 15-palmitoylsolamin 15.16 annopurpuricin-A
19.17 20,23-cis-bullatalicinone 15.17 annopurpuricin-B
6.31 22-epi-calamistrin-B 12.18 annopurpuricin-C
14a.40 24-acetylguanacone 13.32 annopurpuricin-D
13.25 27-hydroxy-bullatacin 3.13 annopurpuricin-E
19.14 28-hydroxy-bullatacinone 7a.6 annoreticuin
14a.52 28-hydroxy-squamocin-l 7a.7 annoreticuinone
19.13 29-hydroxy-bullatacinone 7a.16 annosenegalin
13.11 30-hydroxy-bullatacin 12.10 annosquacin-A
19.8 30-hydroxy-bullatacinone 12.11 annosquacin-B
13.12 31-hydroxy-bullatacin 14a.46 annosquacin-C
19.7 31-hydroxy-bullatacinone 12.12 annosquacin-D
13.13 32-hydroxy-bullatacin 14a.47 annosquacin-I
19.6 32-hydroxy-bullatacinone 17.9 annosquatin-I
7a.24 4-acetylannonacin 16.11 annosquatin-II
9a.14 4-acetylgigantetrocin-A 17.15 annosquatin-III
7a.25 4-acetylxylomaticin 16.12 annosquatin-IV
6.13 4-deoxyannomontacin 17.16 annosquatin-V
6.14 4-deoxyannoreticuin 17.7 annosquatin-A
9b.3 4-deoxycoriacin 17.8 annosquatin-B
17.2 4-deoxygigantecin 14a.54 annotacin
12.16 4-desoxylongimicin-B 5.9 annotemoyin-1
13.29 4-hydroxy-squamocin-Y 5.10 annotemoyin-2
14a.35 6-hydroxy,4-deoxysquamotacin 8.18 araticin
14a.34 6-hydroxy-desacetyluvaricin 13.14 araticulin
8.3 8-hydroxy-annonacin 7a.22 arianacin
1c.30 9,10-dihydrooropheolide 18.2 aromicin
19.18 9-hydroxy-asimicinone 18.1 aromin
14a.49 9-OH-folianin 18.3 aromin-A
19.20 9-oxo-asimicinone 1c.12 artapetalin-A
17.1 almunequin (or squamostatin-A) 1c.13 artapetalin-B
15.12 annocatacin-A 1c.14 artapetalin-C
15.13 annocatacin-B 1a.21 artemoin-A + B + C + D
9a.28 annocatalin 13.1 asimicin
7a.40 annocherimolin 15.2 asimilobin
7a.36 annocherin 14a.8 asimin
10.17 annocherinone 14a.6 asiminacin (or Squamocin-D)
1a.16 annodienin 14a.9 asiminecin
7a.15 annogalene (or xylomatenin) 6.5 asiminenin-A
7a.34 annoglacin-A 6.6 asiminenin-B
7a.35 annoglacin-B 14a.16 asiminocin
13.9 annoglaucin 13.27 asimitrin
8.19 annoglaxin 14a.14 asitribin
8.23 annoheptocin-A 7a.32 asitrilobin-A
8.24 annoheptocin-B 7a.33 asitrilobin-B
8.11 annohexocin 7a.43 asitrilobin-C
1a.14 annojahnin 7b.12 asitrilobin-D
9a.21 annomolin 7a.41 asitrocin
11b.12 annomolon-A + 34-epi 10.18 asitrocinone
11b.13 annomolon-B + 34-epi 14a.26 atemotetrolin
8.1 annomonicin 14a.45 atemoyacin-B
7a.5 annomontacin 13.26 atemoyacin-C
10.11 annomontacinone 15.14 atemoyacin-E
7a.37 annomontanin-A 14a.12 bullacin
8.20 annomontanin-B 14a.33 bullacin-B
11b.7 annomontanin-C 15.9 bulladecin
8.4 annomuricin-A 19.5 bulladecinone
8.5 annomuricin-B 14a.11 bullanin
8.10 annomuricin-C 13.3 bullatacin (or rolliniastatin-2)
8.16 annomuricin-E 19.1 bullatacinone
10.9 annomuricinone-D 16.3 bullatalicin (or cherimolin-1)
(continued on next page)

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A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 13 (continued) Table 13 (continued)

19.3 bullatalicinone (or isocherimolin-1) 3.5 dieporeticenin

16.4 bullatanocin (or cherimolin-2) 3.12 dieporeticenin
19.4 bullatanocinone 3.10 dieposabadelin
5.6 bullatencin 3.6 diepoxymontin
14a.17 bullatetrocin 3.8 diepoxyrollin
14a.10 bullatin 7a.26 disepalin
1c.3 buthyrolactone-1 1a.12 donbutocin
1c.4 buthyrolactone-2 1a.19 donhepocin +34-epi
6.17 calamistrin-A 1a.11 donhexocin
6.18 calamistrin-B 8.15 donnaienin
6.21 calamistrin-C 11b.1 donnaienin-A + 34-epi
6.22 calamistrin-D 11b.2 donnaienin-B + 34-epi
6.23 calamistrin-E 11b.6 donnaienin-C + 34-epi
14b.7 calamistrin-F 1a.20 donnaienin-D + 34-epi
14b.8 calamistrin-G 5.21 dotistenin
1c.15 cananginone-A 2.1 epomuricenin-A or epoxymurin-A
1c.16 cananginone-B 2.3 epomuricenin-B
1c.17 cananginone-C 2.7 epomurinin-A
1c.18 cananginone-D 2.8 epomurinin-B
1c.19 cananginone-E 2.4 epomusenin-A
1c.20 cananginone-F 2.5 epomusenin-B
1c.21 cananginone-G 2.1 epoxymurin-A (or epomuricenin-A)
1c.22 cananginone-H 2.2 epoxymurin-B
1c.23 cananginone-I 2.10 epoxyrolin-B
14a.23 carolin-A 14b.4 espelicin
14a.24 carolin-B 12.13 folianin-A
14a.25 carolin-C 12.14 folianin-B
22b.3 chamuvarinin 1a.9 gardnerilin-A
1c.5 chatenaytrienin-1 + 2 1a.10 gardnerilin-B
1c.6 chatenaytrienin-3 + 4 11b.5 gardnerinin +34-epi
16.3 cherimolin-1 (or bullatalicin) 6.4 giganenin
16.4 cherimolin-2 (or bullatanocin) 1a.1 giganin
6.15 cis-4-deoxyannoreticuin 16.2 gigantecin
7a.39 cis-annomontacin 19.16 gigantecinone
7a.19 cis-annonacin 9a.1 gigantetrocin-A
7a.20 cis-annonacinone 9a.4 gigantetrocin-B
7a.46 cis-annoreticuin 10.6 gigantetrocinone
5.20 cis-annotemoyin-1 9a.3 gigantetronenin
5.19 cis-bullatencin 10.10 gigantetroneninone
6.28 cis-corossolone (CO,10) 7b.8 gigantransenin-A + B
9b.4 cis-gigantrionenin 7b.9 gigantransenin-C
11b.4 cis-goniodonin + 34-epi 9b.1 gigantriocin
7a.21 cis-goniothalamicin 9b.2 gigantrionenin
8.27 cis-montacin 15.10 glabracin-A
6.7 cis-murisolin 15.11 glabracin-B
5.12 cis-panatellin 9a.17 glabranin
5.15 cis-reticulatacin 7a.29 glacin-A
6.16 cis-reticulatacin-10-one 7a.30 glacin-B
5.11 cis-solamin 6.19 glaucabellin
5.14 cis-uvariamicin-I 9a.16 glaucafilin
5.13 cis-uvariamicin-IV 13.22 glaucanetin
1a.6 cohibin-A 13.10 glaucanisin
1a.7 cohibin-B 21.1 goniocin
1a.15 cohibins-C + D 15.1 goniodenin
3.2 corepoxylone 11b.3 goniodonin +34-epi
9a.9 coriacin 7a.13 gonionenin
9b.7 coriacyclodienin 10.16 gonioneninone
9b.8 coriacycloenin 7a.31 goniotetracin
1a.3 coriadienin 7a.2 goniothalamicin
8.13 coriheptocin-A 10.7 goniothalamicinone
8.14 coriheptocin-B 1c.9 goniothalamusin
14a.48 cornifolin 16.10 goniotriocin
3.9 coronin 9a.18 goniotrionin
6.2 corossolin 1c.34 gracilipin-A
6.3 corossolone 14a.21 guanacone
1c.24 debilisone-A 14a.41 guanaconetin-1
1c.25 debilisone-B 14a.42 guanaconetin-2
1c.26 debilisone-C 14a.43 guanaconetin-3
1c.27 debilisone-D 14a.44 guanaconetin-4
1c.28 debilisone-E 10.1 isoannonacin
1c.29 debilisone-F 10.2 isoannonacinone
9a.2 densicomacin-1 10.4 isoannoreticuin
12.2 desacetyluvaricin 19.3 isocherimolin-1 (or bullatalicinone)
3.1 diepomuricanin-A 12.4 isodesacetyluvaricin
3.7 diepomuricanin-B 13.30 isolongimicin-B
3.3 dieporeticanin-1 19.9 isomolvizarin-1
3.4 dieporeticanin-2 19.10 isomolvizarin-2
(continued on next page)

27
A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 13 (continued) Table 13 (continued)

10.12 isomurisolenin 9a.27 muricin-F

14a.2 isorollinicin 7a.42 muricin-G
19.2 itrabin 9b.5 muricin-H
1a.17 jahnonacin 9b.6 muricin-I
7a.22 javoricin 7a.56 muricin-J
11a.1 jetein 7a.57 muricin-K
22b.2 jimenezin 9a.35 muricin-L
12.15 joolanin (CO,5) 9a.34 muricin-M
20.1 laherradurin 7a.54 muricin-N
5.16 laurifolin 9a.36 muricin-O
5.22 lepirenin 9a.19 muricoreacin
1b.3 longanin 1c.1 muridienin-1
7a.17 longicin 1c.2 muridienin-2
6.12 longicoricin 1c.8 muridienin-3 + 4
6.11 longifolicin 9a.10 murihexocin-A + B
13.18 longimicin-A 9a.20 murihexocin-C
13.19 longimicin-B 1a.13 murihexol
13.20 longimicin-C 6.1 murisolin
14a.18 longimicin-D 6.8 murisolin-A
12.5 membranacin 10.8 murisolinone
12.9 membrarollin 14b.2 narumicin-I
1c.35 methylsaccopetrin-A 14b.3 narumicin-II
14a.36 microcarpacin-A 12.3 neoannonin
14a.37 microcarpacin-B 2.9 neo-epoxyrolin
1c.31 mitregenin 14a.28 ophrypetalin
13.4 molvizarin 1c.32 oropheolide
9a.29 monlicin-A 20.3 otivarin
9a.30 monlicin-B 14b.1 panalicin
8.26 montacin 11b.11 parisin
6.24 montalicin-A 16.5 parvifloracin
6.25 montalicin-B 13.8 parviflorin (or squamocin-E)
7a.44 montalicin-C 7b.15 plagioneurin-A
7a.45 montalicin-D 7b.16 plagioneurin-B
7a.47 montalicin-E 7b.17 plagioneurin-C (CO,10)
7a.48 montalicin-F 7b.18 plagioneurin-D (CO,10)
8.28 montalicin-G 7b.19 plagioneurin-E (CO,10)
8.29 montalicin-H 6.29 plagionicin-B (CO,10)
7a.49 montalicin-I 8.30 plagionicin-C
7a.50 montalicin-J 7b.1 plagionicin-A
8.2 montanacin 7b.14 plagionicin-D (CO,5)
8.21 montanacin-B 13.24 purpuracenin
8.22 montanacin-C 13.7 purpureacin-2
22c.2 montanacin-D 14a.27 purpurenin
22c.3 montanacin-E 22a.2 pyragonicin
10.22 montanacin-F 22a.1 pyranicin
10.21 montanacin-G 7a.11 reticulacinone
11b.8 montanacin-H + 34-epi 5.2 reticulatacin (or uvariamicin-II)
11b.9 montanacin-I + 34-epi 5.7 reticulatain-1
11b.10 montanacin-J + 34-epi 5.8 reticulatain-2
1a.5 montecristin 1b.1 reticulatamol
7a.27 mosin-B 1b.2 reticulatamone
7a.28 mosin-C 13.6 rioclarin
10.13 mosinone-A 15.15 robustocin
14a.4 motrilin (or annonin-III) 7a.38 rolliacocin
22c.1 mucocin 1d.1 rollicosin
22b.1 muconin 15.4 rollidecin-A
14a.19 mucoxin 15.5 rollidecin-B
1c.7 muricadienin 15.7 rollidecin-C
8.17 muricapentocin 15.8 rollidecin-D
8.12 muricatalicin 13.21 rollimembrin
9a.11 muricatalin 14a.30 rollimusin
8.25 muricatatin-C 15.6 rollinacin
1a.18 muricatenol 7a.23 rollinecins-A + B
9a.5 muricatetrocin-A + B 13.2 rolliniastatin-1
9a.15 muricatetrocin-C 13.3 rolliniastatin-2 (or bullatacin)
9a.7 muricatin-A 19.2 rollinone
9a.8 muricatin-B 14a.20 rollitacin
8.6 muricatin-C 2.6 sabadelin
8.7 muricatocin-A 1c.10 saccosetrin-A
8.8 muricatocin-B 1c.11 saccopetrin-B
8.9 muricatocin-C 14a.29 salzmanin
7a.55 muricenin (Δ21) 14a.38 salzmanolin
9a.22 muricin-A 9.A8 senegalene
9a.23 muricin-B 5.4 solamin
9a.24 muricin-C 7b.10 sootepensin-A
9a.25 muricin-D 7b.11 sootepensin-B
9a.26 muricin-E 14a.22 spinencin
(continued on next page)

28
A. Neske, et al. Phytochemistry 174 (2020) 112332

Table 13 (continued) Table 13 (continued)

8.31 squadiolin A 1a.8 venezinone

9b.9 squadiolin-B 7a.15 xylomatenin (or annogalene)
9a.31 squadiolin-C 7a.10 xylomaticin
7b.20 squafosacin B 10.15 xylomaticinone
6.30 squafosacin C 7a.9 xylopiacin
5.23 squafosacin-F 7a.8 xylopianin
5.24 squafosacin-G 7a.14 xylopien
3.11 squamocenin-A 1c.33 xymarginatin
5.25 squamocenin-B
14a.1 squamocin
14a.55 squamocin IV
4.5. Tri-THF ACGs (Group 21)
6.32 squamocin V
14a.5 squamocin-B
14a.6 squamocin-D (or asiminacin) There is no described tri-THF ACG in the 2005–2019 period
13.8 squamocin-E (or parviflorin) (Table 10).
14a.7 squamocin-F
12.6 squamocin-I
13.28 squamocin-1 4.6. THP ACGs (Group 22)
14a.50 squamocin-II
14a.51 squamocin-III It is included in the group of ACG characterized by an atypical
12.7 squamocin-K
substituted alkyl chain with tetrahydropyran (THP) ring systems.
12.8 squamocin-N
14a.31 squamocin-O1
14a.32 squamocin-O2 5. Biological activities and action mechanism of ACGs
14a.3 squamocinone
14a.53 squamocin-P
19.19 squamolinone Annonaceous ACGs are very interesting compounds due to their
10.3 squamone well-known cytotoxic activity. In fact, uvaricin, the first isolated ACG
17.10 squamostanin-A (Bermejo et al., 2005), was announced as a new antitumor compound.
17.11 squamostanin-B
Since then, ACGs have always been judged as promising candidates for
17.12 squamostanin-C
17.13 squamostanin-D a future generation of drugs to fight against current chemotherapy-re-
17.1 squamostatin-A (or almunequin) sistant tumors.
17.14 squamostatin-C Although ACGs have exhibited diverse biological activities, in-
17.3 squamostatin-D cluding antibacterial (Cartagena et al., 2007), insecticidal (Alvarez
17.4 squamostatin-E
Colom et al., 2010; Di Toto Blessing et al., 2015, 2012, 2010; Ruiz
7a.12 squamosten-A
7a.58 squamosten-B Hidalgo et al., 2018; 2016; Tolosa et al., 2014, 2012), cytotoxic
1d.2 squamostolide (Bermejo et al., 2005), immunosuppressive effects (Rupprecht et al.,
14a.57 squamotin-A 1990), stimulation of the bacterial biofilm (Alessandrello et al., 2017;
12.19 squamotin-B
Parellada et al., 2017, 2013, 2012, 2011), neurotoxic (Höllerhage et al.,
12.20 squamotin-C
14a.58 squamotin-D 2009; Gibson et al., 2010; Champy et al., 2009) and green corrosion
10.14 squamoxinone inhibitor (Alvarez et al., 2018), investigators have developed a parti-
10.19 squamoxinone-B cular interest on their potential anticancer effects and on their under-
10.20 squamoxinone-C lying mechanisms of activity.
6.27 squamoxinone-D
13.31 squamoxinone-E
16.1 sylvaticin 5.1. Interaction of ACGs with artificial lipid membranes
6.10 tonkinecin
1a.4 tonkinelin
In 1991, Londershausen et al. (1991) established that the me-
7b.5 tonkinesin-A
7b.6 tonkinesin-B chanism of cytotoxic action of ACGs consisted mainly in the inhibition
7b.7 tonkinesin-C of mitochondrial complex I and more specifically in the inhibition of
7b.2 tonkinin-A mitochondrial electron transport. This implies the loss of the ability to
7b.3 tonkinin-B
form ATP by the cell and inhibits cellular respiration, which explains
7b.4 tonkinin-C
13.5 trilobacin why such activity occurs although the mechanism of selective cyto-
19.15 trilobacinone toxicity and the factors that modulate its effectiveness against both
16.9 trilobalicin cancer cells are unknown.
14a.13 trilobin The number of inhibitors continues to grow steadily, making it
4.1 tripoxyrollin
impossible to classify them chemically. There are synthetic and com-
20.4 tucumanin
9a.32 tucupentol mercial inhibitors including agrochemical products used as insecticides
14a.15 uleirollin and acaricides, as in the case of pyridaben (Hollingworth and
5.1 uvariamicin-I Ahammadsahib, 1995). There are also natural inhibitors; one of the
5.2 uvariamicin-II (or reticulatacin)
most representative is rotenone, which has been used as an insecticide
5.3 uvariamicin-III
5.5 uvariamicin-IV
for a century and a half to control leaf-eating caterpillars and for over
14b.5 uvariasolin-I three centuries as a selective piscicide at doses that are relatively non-
14b.6 uvariasolin-II toxic to organisms that serve as food for fish and degrade rapidly. Also,
6.26 uvaribonianin we can highlight the piericidin, a natural antibiotic produced by various
7b.13 uvaribonin
strains of Streptomyces. However, ACGs isolated from Annonaceae
12.1 uvaricin
6.9 uvarigranin species are the most potent inhibitors of complex I (Degli Esposti et al.,
6.20 uvarigrin 1994). A series of studies have been conducted that allowed researchers
1a.2 venezenin to postulate how ACG interacts with complex I, as many groups have
worked with these inhibitors in order to establish the necessary

29
A. Neske, et al.
requirements for their maximum activity.
Shimada et al. (1998a, 1998b) established that the THF rings should
interact strongly with the polar ends of phospholipids in the liposome
membranes and suggested that these THF rings act as a hydrophilic
anchor to the membrane to optimize the position and conformation of
the functional groups of ACG, the terminal lactone being a part of the
domain spacer, the part of the molecule which would interact directly
with the active site of the enzyme in the complex I, through a lateral
diffusion in the inner mitochondrial membrane.
Based on the large number of specific inhibitors (natural or syn-
thetic) existing with so different structures between them, the active
center of the enzyme is postulated to differ substantially from the
classic key-lock model and has become more like a large cave, probably
formed by several protein subunits capable of holding such different
compounds chemically.
Results obtained by Barrachina et al. (2004), show that the bis-THF
ACGs are more active than mono-THF as inhibitors of the mitochondrial
respiratory chain (CRM) and at the same time more active than rote-
none.
Membrane environment determines and limits the conformations
and the location of lipophilic compounds acting at a membrane re-
ceptor in the lipid bilayer. Therefore, to determine the interactions of
these ACGs in those membranes seems to be necessary to understand
their role as potent cytotoxic compounds. Previous results have in-
dicated that the effects caused by certain compounds on the hydration
patterns surrounding phosphate and carbonyl groups of phospholipids
can be studied by FTIR spectroscopy (Diaz et al., 2001, 1999; Hübner
and Blume, 1998).
Recently, Bombasaro et al. (2011) analyzed the interaction of ACGs
and analogues with POPC bilayers in hydrated states by FTIR. They
observed the behavior in artificial membrane of POPC bilayers for
natural mono THF ACGs and synthetic analogues such as THF. They
have analyzed the intermolecular interactions between the lipid head-
groups (glycerol and phosphate) of POPC and the THF/flanking hy-
droxyls of ACGs. The FTIR results revealed intermolecular interactions
between the headgroups of POPC (specifically phosphate groups) and
the hydroxylated-THF of ACGs mono and bis THF. These interactions
indicated that the phosphate groups of the lipid membrane form
stronger hydrogen bonds with hydroxylated-THF rings of ACGs than
with water molecules, which suggests a strong dehydration in its en-
vironment.
In order to better understand the molecule details of these interac-
tions, Bombasaro et al. (2011) performed Molecular Dynamics (MD)
simulations in which ACGs interact with POPC in the fully hydrated
state of the lipid. These simulations emphasize the role of the THF rings
through their flanking hydroxyl groups to form hydrogen bond inter-
actions acting as hydrophilic anchor in the lipid membrane. Results
revealed intermolecular interaction between the headgroup of POPC
(specifically phosphate groups) and the hydroxylated-THF of the ACGs.
These interactions indicated that the phosphate groups of the lipid
membrane form stronger hydrogen bonds with hydroxylated-THF rings
of ACGs than with water molecules. This suggests that there is a strong
dehydration in its environment. These results reveal that the OH groups
of ACGs might preferably associate with the phosphate groups of
membranes in the liquid crystalline state.
These results could be regarded as interesting complementary data
for FTIR measurements which are in complete agreement with previous
reported simulations (Bombasaro et al., 2008). They give an additional
support for the stepwise binding mechanism proposed by Shimada et al.
(1998a, 1998b). The membrane environment determines and limits the
conformations and the location of lipophilic compounds acting at a
membrane receptor in the lipid bilayer. The toxicity of ACGs would
seem to be strongly related to the membrane conformation (Shimada
et al., 1998a, 1998b).
The destabilization that occurs in the membrane due to dehydration
around the phosphate groups caused by interaction with ACGs allowed
30
Phytochemistry 174 (2020) 112332
the understanding of the action mechanism of ACGs in the membrane
environment (Bombasaro et al., 2011). In addition, it suggests that it
would be another reason for which ACGs exert their biological action,
specifically the insecticide action (Di Toto Blessing et al., 2012).
5.1.1. Replacement of the hydroxyl group on the aliphatic chain and
flanking THF
Di Toto Blessing et al. (2015) reported structural modifications on
the natural ACGs, blocking the OH flanking THF, with MOM and
OCOCH3. They evaluated the toxic and nutritional effects of ACGs and
their semisynthetic analogues on the lepidopteran Spodoptera frugiperda
Smith. Results allowed them to suggest that the capacity-donor hy-
drogen bonding of the hydroxyl group acts as a hydrophilic anchor on
the surface of the liposomal membrane and this result would explain
the biological activity that ACGs display. They conclude that the OH
groups and/or OCOCH3 flanking the THF are essential structural fac-
tors for the intermolecular interaction with the hydrophilic polar head
groups of the membrane. Then, they suggest that this intermolecular
interaction is the mechanism by which ACG produces dehydration of
the membrane and may then enhance bioactivity by restricting the lo-
cation, conformation and orientation of the ACG (Di Toto Blessing
et al., 2015).
This study emphasizes the role of the flanking OH and acetyl groups
of THF with the membrane hydrophilic polar head groups. They are
essential structural factors in the ACG that facilitate the intermolecular
interaction that dehydrates the membrane and makes it potentially
toxic.
It is noteworthy that knowledge based on both approaches, ex-
perimental and theoretical, will increase the comprehension of the
ACGs action mechanism in the artificial lipid membranes of POPC
(Fig. 3).
Thus, to know the structural requirements of ACGs in causing
toxicity brings us closer to understanding the “pharmacophore” which
will allow us to design more active synthetic derivatives.
5.2. ACGs as bacterial biofilm promoters
Bacterial biofilms are clusters of cells that grow attached to a sur-
face or interface and are frequently embedded within a self-produced
matrix of extracellular polymeric substance (EPS) (Singh et al., 2006).
Biofilm formation is often regulated by a cell density-dependent sig-
naling system called quorum sensing. In quorum sensing, bacteria
monitor their own population density through the production, release
and detection of molecules called type 1 autoinducers (AI-1) which in
Gram negative bacteria are N-acyl-homoserine lactones (AHLs) (Bassler
and Losick, 2006). AHLs play an important role in the regulation of
biofilm formation in some bacteria (Waters and Bassler, 2005).
Polycyclic aromatic hydrocarbons (PAHs) are a diverse class of
hydrophobic organic compounds consisting of two or more fused aro-
matic rings. Due to their carcinogenic, mutagenic and toxic properties,
some PAHs are considered priority pollutants for remediation by the
Environmental Protection Agency United States (EPA) and the
European Environment Agency (Keith and Telliard, 1979; Smith et al.,
1989). Among PAHs, naphthalene has been commonly taken as a model
compound for biodegradation studies (Ferrero et al., 2002).
ACG (Fig. 4a) and AHLs (Fig. 4b), structurally share the γ-lactone
moiety. Besides, they have a long, lipophilic carbon chain and are,
therefore, expected to be quantitatively associated with membranes.
Previous reports determined the positions of both THF and lactone
rings within liposomal membranes by proton (1H) nuclear magnetic
resonance spectroscopy. They proposed that THF rings with their
flanking hydroxyl groups act as a hydrophilic anchor in the lipid
membrane, while the terminal carbon chain of lipophilic nature inter-
acts with the acyl side chains of phospholipids (Bombasaro et al., 2011;
Di Toto Blessing et al., 2012; Shimada et al., 1998b). Hydrocarbons
tend to reside within the hydrophobic region between membrane
A. Neske, et al.
Fig. 3. ACGs mechanism of action in the artificial lipid membranes of POPC.
monolayers composed by the acyl chains of phospholipids. Many bac-
teria, in response to this situation, form biofilms, and would express a
phenotype of general response to stress (Van Hamme et al., 2003). In
addition, the specific interaction sites of ACG with 1-palmitoyl-2-
oleoyl-synglycero-3-phosphatidylcholine (POPC) lipidic bilayers (FTIR
spectrometry) have been reported (Bombasaro et al., 2011).
Parellada et al. (2017, 2013, 2012, 2011) have first reported both
the natural and structurally modified ACGs, the stimulating ability of
biofilm formation in degrading bacteria of PAHs at a very low con-
centration (2.5 mg mL−1).
These results led them to the search for bio-remediator bacteria that
developed biofilm for environmental control. Among them, the
Pseudomonas, represent an efficient and safe alternative for the bio-
remediation of naphthalene used as model of PAHs.
The differences in the consumption of naphthalene by the bacterial
strain in the presence and absence of ACGs are due to the fact that from
the start of degradation, they exist in a larger number of treated cells in
the state of biofilm which are capable of consuming the present naph-
thalene more quickly than in the absence of ACGs.
Then, they thought that as ACGs have a long hydrocarbon chain of
Fig. 4. ACG and AHLs.
31
Phytochemistry 174 (2020) 112332
hydrophobic nature, they would be expected to behave as hydrocarbons
that tend to reside in the hydrophobic area between the monolayers of
the membrane in the acyl chains of phospholipids, which causes the
change of the structure and the bacterium in response to this stressful
situation to form biofilm. Their research led them to conclude that: a)
ACGs are stressors that increase in Gram negative bacteria, the N-acyl-
homoserine lactone (AHL) synthesis and thus increase the biofilm for-
mation (Fig. 5), and b) the increase of the biofilm formation leads to the
increase of naphthalene degradation. Naphthalene consumption rate
has been tripled in the presence of ACGs. This fact could be employed to
increase biofilm formation and effectiveness of PAHs bioremediation
(Parellada et al., 2013).
ACGs are indirectly involved in the quorum sensing mechanism by
inducing a stress related to the increase in AI production which, in turn,
results in more biofilm formations. These ACGs could not be found in
any of the supernatants, but they were successfully isolated from bac-
terial pellet extracts (obtained from cell cultures grown in their pre-
sence). ACGs are associated with cellular material (Parellada et al.,
2013).
The results of the analysis of cells and supernatants obtained from
A. Neske, et al.
Fig. 5. The ACGs act only as stressors.
cell cultures by chromatographic techniques (TLC revealed with
Kedde's reagent and RP-HPLC) and mass spectrometry (EI-MS) allowed
Parellada to determine that ACGs are located in the bacterial pellet, as
was expected given their theoretical log p values.
A summary of the results of chromatographic and spectroscopic
methods employed involves the formation of a pink magenta compound
by reaction with Kedde's reagent, a coincidence or similarity in reten-
tion times during a chromatographic run or an excellent correlation
between fragmentation patterns as shown in Fig. 6.
The localization of the ACGs, without structural modifications in the
bacterial pellet extracts, corroborates that they act only as stressors. The
log p values suggest that ACG might reside in the lipid membranes of
cells. Thus, results suggest that these ACGs act as bacterial membrane
natural stressors (Parellada et al., 2013).
These results allow to consider promising ACGs in environmentally
safe bioremediation conditions.
5.3. Neurotoxic activities
Annonaceous acetogenins have shown a large variety of biological
activities including pesticidal, antimicrobial, insecticidal, antiparasitic,
fungicidal, herbicidal and antitumor properties. One of the most pro-
minent effects of ACGs is their cytotoxicity by inhibiting the growth of
various cell lines and human cancer cells via inhibition of mitochon-
drial respiratory chain Complex I (MRC) (Höllerhage et al., 2009). This
effect on electron transport chain makes them promising agents in the
field of pharmacological and agrochemical research. In recent years,
complex I has aroused great interest because the development of several
degenerative diseases with congenital or acquired effects appears to be
32
Phytochemistry 174 (2020) 112332
associated with this complex. In general, dysfunctions of complex I
mainly affect those organs which have higher ATP demands such as the
central nervous system and skeletal muscles.
In the study of neurodegenerative diseases, it is essential to have in
vivo adequate models capable of reproducing the major symptoms of
these pathologies. To date, there are several experimental neurotoxic
models, including 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP), paraquat and rotenone, however,
they have significant limitations (Gibson et al., 2010). On the basis of
epidemiological data, the tendency to use toxins of natural origin-based
models of PD seems to be attractive, and has triggered numerous public
debates on the etiology of the disease. Höllerhage et al. (2009), re-
ported that lipophilic inhibitors of complex I of natural or synthetic
origin can give tauopathy in vitro, so a search for new models based on
naturally occurring toxins such as ACGs may have a strong implication
in the design of new experimental models of these pathologies.
For the last 20 years, numerous evidences have indicated that many
human diseases have their cause, or are related, in some way, to al-
terations in the folding of specific proteins and their accumulation in
the form of aggregates. Both the loss of function of these proteins due to
an incorrect folding and their cytotoxic properties as aggregates are two
fundamental pathogenic mechanisms of neurodegenerative diseases
such as Parkinson's and Alzheimer's diseases (Van Hamme et al., 2003;
Dobson, 2004). Two events have given a new direction to research on
the etiology and pathogenesis of these diseases: firstly, genetic dis-
coveries that relate the early condition of rare Parkinson's disease (PD)
to the triplication of the gene encoding for α-synuclein (AS) (protein of
140 amino acids located in the presynaptic terminals) and with three
point mutations of the same gene (A30P, E46K, A53T) (Conway et al.,
A. Neske, et al.
Fig. 6. Chromatographic and spectroscopic methods employed. Results summary: Involves the formation of a pink magenta compound by reaction with Kedde's
reagent, coincidence or similarity in retention times during a chromatographic run or excellent correlation between fragmentation patterns.
2000; Eliezer et al., 2001; Uéda et al., 1993). Secondly, the identifica-
tion of AS protein as the main component of Lewy's bodies and Lewy's
neurites, neuropathological inclusions characteristic in all types of PD
and several other diseases (Forno, 1996; Iwai et al., 1995; Jakes et al.,
1994). Lewy's bodies and Lewy's neurites are in a state of highly or-
dered aggregation called fibrillar or amyloid aggregate. Preamyloid
oligomers of AS are toxic species that cause neuronal damage (Moore
et al., 2005; Uversky, 2007), whereas fibrillar species are apparently
non-toxic and could play a protective role (Bucciantini et al., 2002).
Tau is a microtubule-associated protein (Maccioni and Cambiazo,
1995). In certain diseases, Tau is hyperphosphorylated to lead to its
intracellular accumulation in the form of neurofibrillary tangles. Toxic
interactions with AS contribute to hyperphosphorylation of tau, leading
finally to the deposition of both proteins. These findings have placed
the dysfunction of both AS and tau proteins in the common focus of
several neurodegenerative diseases. Numerous AS in vitro aggregation
inhibitors were tested in cell cultures with little encouraging results and
only few inhibitors are in clinical phase development (Bulic et al., 2010;
El-Agnaf et al., 2004; Lindgren and Hammarström, 2010).
In Guadeloupe (French Antilles), epidemiological data have related
the atypical PD to fruit and herbal teas of plants of the Annonaceae
family, particularly Annona muricata L. (Caparros-Lefebvre and Elbaz,
1999; Caparros-Lefebvre et al., 2002). The biological effects that ACGs
exert on cells are strongly conditioned by the interaction of ACGs with
the cell membranes, the alterations they cause to the membrane sta-
bility, the ability of ACGs to diffuse into the membranes, and the
functional groups of ACGs as anchor sites.
The ACGs mode of action has always been the subject of numerous
studies. ACGs selectively inhibit complex I of MRC (Londershausen
et al., 1991).
33
Phytochemistry 174 (2020) 112332
Complex I is the first protein component of MRC and plays an im-
portant role in the ATP production and the mitochondrial function, in
general. Mitochondrial dysfunction has been identified in a series of
neurodegenerative diseases (Höllerhage et al., 2009). Mitochondrial
toxins are capable of producing certain selectivity in neuronal cell
death, being used to produce models of human neurodegenerative
diseases (Champy et al., 2004).
Annonacin, an ACG isolated from the fruit, bark and leaves of
Annona muricata is a compound that exhibits activity related to the
inhibition of electron transport in the MRC (Bermejo et al., 2005; Degli
Esposti et al., 1994) and has been assigned as the cause of parkinsonian
disorder in Guadalupe (Caparros-Lefebvre and Elbaz, 1999; Caparros-
Lefebvre et al., 2002; Champy et al., 2004). Studies in the area have
reported that annonacin causes cell death and abnormal tau aggrega-
tion in mesencephalon cultures (Escobar-Khondiker et al., 2007;
Höllerhage et al., 2009; Lannuzel et al., 2003) and neurodegeneration
of the basal ganglia and the brainstem after intravenous administration
to rats (Champy et al., 2004). These results suggest that ACGs would
participate in the pathogenesis of neurodegenerative diseases.
The Annonaceae have been investigated not only for their potential
in cancer treatments (Liaw et al., 2010; McLaughlin, 2008), but also for
their neurotoxicity (Champy et al., 2004; Lannuzel et al., 2006) due to
the high content in ACGs (Champy et al., 2009, 2005).
Potts et al. (2012) reported a similar work; they studied the effect of
annonacin, isolated from Asimina triloba fruit in cortical neurons. Re-
sults showed that annonacin is less potent in cortical neurons than
previously reported in the mesencephalon and striatum neurons
(Escobar-Khondiker et al., 2007; Höllerhage et al., 2009).
To date, the toxicity of ACGs has only been documented in cancer
cell lines and in experimental models of cancerous mice (McLaughlin,
A. Neske, et al.
2008). The finding of in vitro cortical neurotoxicity corroborates the
neurotoxicity of annonacin in substantia nigra as reported (Champy
et al., 2004; Escobar-Khondiker et al., 2007; Lannuzel et al., 2002).
It is worthy to notice that the syndrome of atypical parkinsonian
disorder is produced by the consumption in the diet of high con-
centrations of ACGs, typical of tropical fruits (Caparros-Lefebvre and
Elbaz, 1999; Caparros-Lefebvre et al., 2002; Lannuzel et al., 2007).
The AS polymerization from unstructured monomer to mature
amyloid fibrils rich in beta sheet structures is known to occur through
the formation of several oligomers and polymers of altered sizes. The
presence of these pathological inclusions of AS is one of the crucial
characteristics of several neurodegenerative diseases, including de-
mentia and multisystemic atrophy (Duda et al., 2000; Goedert, 2001;
Spillantini et al., 1998). AS inclusions are also found in a significant
percentage of other neurodegenerative disorders, including neurode-
generation with cerebral Iron accumulation, Down syndrome, pro-
gressive autonomic dysfunction, and also familiar as well as sporadic
Alzheimer's disease (Arai et al., 2000; Arawaka et al., 1998; Hamilton,
2000; Lippa et al., 1999).
D'Hiriart (2016) studied the effect of cytotoxic ACGs on the ag-
gregation of AS. ACGs are involved in this process by altering the ki-
netics of aggregation. The study of ACG molecules that are in vivo able
to induce atypical parkinsonian syndrome, such as that occurring in
Guadalupe (Lannuzel et al., 2007), is an alternative strategy in the
search for an experimental model of the disease. He reported, for the
first time, the modification that occurs in the spontaneous aggregation
of AS in the presence of an ACG. The increase in the rate of aggregation
of AS and the enrichment in toxic oligomers in the presence of anno-
nacin concludes with the formation of mature fibers. These integrate
Lewy's bodies that interfere with normal cellular processes with con-
sequent neuronal death.
In this context, the structural and functional characteristics of the
aggregation products of these proteins are essential to be studied. These
oligomers are responsible for cell death in PD.
5.4. Pesticidal activities
Spodoptera frugiperda (J.E. Smith) is a polyphagous lepidopteran
commonly called fall armyworm, a major pest in corn fields where it
feeds on leaves, tassels and ears of corn (Marenco et al., 1992). Severe
damages are particularly caused during its early larval stages (Murúa
and Virla, 2004).
Annonaceous acetogenins belonging to the Annonaceae family re-
present a class of bioactive compounds whose toxic effects have been
reported for several species of insects. Given their insecticidal proper-
ties, Ruiz Hidalgo et al. (2016) first carried out the isolation of ACG
from a Brazilian collection of seeds of Annona squamosal L. (Annona-
ceae) and prepared their methoxy methylated (MOM) and acetylated
(OAc) derivatives by chemical methods. They reported the study of the
antifeedant, toxic and nutritional effects of three natural acetogenins
and their acetylated and methoxy methylated derivatives on Spodoptera
frugiperda Smith (Lepidoptera: Noctuidae). Natural ACGs, squamocin
and molvizarin, killed 100% of S. frugiperda Smith larvae, followed by
motrilin (80%). Acetylated derivatives had less toxic and nutritional
effects than natural ACGs which led to pupal mortality and adult fatal
malformations. The addition of MOM derivatives to the larval diet has
no toxic effects on larvae, but significantly reduces growth rate and
efficiency in the conversion of ingested food into biomass, affecting
adult survival (Ruiz Hidalgo et al., 2016).
Previous results from other researchers indicated that some acet-
ogenins from Annona cherimolia Mill. and A. montana Macfad. have
larvicidal effects on the Spodoptera frugiperda Smith (Lepidoptera) corn
pest (Alvarez Colom et al., 2010, 2008, 2007), nymphal and adult
mortality on the Oncopeltus fasciatus Dallas (Hemiptera) cotton pest
(Alvarez Colom et al., 2008), and insecticidal activity against Ceratitis
capitata Wiedemann (Diptera) (Alvarez Colom et al., 2010).
34
Phytochemistry 174 (2020) 112332
The ACGs structurally transformed by acetylation showed less
toxicity than natural ACGs. The most important toxic action was ob-
served in natural ACG against S. frugiperda Smith larvae at the dosis
tested, following acetylated and MOM derivatives. These results are in
agreement with a previous report from our team for other ACGs isolated
from different species of Annonaceae (Di Toto Blessing et al., 2015).
Ruiz Hidalgo et al. (2018) reported the biocide effects of natural
ACGs from Annona squamosal L., A. muricata L. and A. montana Macfad
seeds on Spodoptera frugiperda Smith (Lepidoptera: Noctuidae). Also,
some acetylated and methoxy methylated ACGs derivatives were syn-
thesized and evaluated. Natural acetogenin rolliniastatin-2 (100 μg g−1
of diet) produced the most important toxic action causing 100% mor-
tality of early instar larvae. Derivatization of ACG yielded compounds
that produced nutritional alterations. The incorporation of roll-
iniastatin-2 (3 OAc) and rolliniastatin-2 (3 MOM) (100 μg g−1) into the
artificial diet of S. frugiperda Smith exhibited the strongest antifeedant
effects causing a marked decrease in larval growth and adult lethal
malformations. Natural ACGs are promising specialised metabolites for
insect control. Derivatization of these compounds reduces their toxicity
to early instar larvae (Ruiz Hidalgo et al., 2018).
They found that natural ACGs containing adjacent bis-THF groups
were more active than those with non-adjacent groups. Moreover,
compounds with a single THF group were also less active, except for
compound cis-annonacin. The structural characteristics of the lactonic
group also seem to be significant. Adjacent bis-THF ACG with β-hy-
droxylated lactone groups had less activity than those with unsaturated
lactone groups.
The natural ACG rolliniastatin-2 (100 μg g−1 of diet) produced the
most important toxic action causing 100% mortality of early instar
larvae. Acetylation and methoxy-methylation of ACG reduced their
toxicity and caused malformations and size decrease in surviving
adults, which led them to death before laying eggs (Ruiz Hidalgo et al.,
2018).
Nutritional effects were assessed in order to infer the action me-
chanism leading to mortality. Decreases in ECI values for natural ad-
jacent bis-THF ACG and acetylated bis-THF ACGs are consistent with
chronic intoxication leading to death, thus preventing the production of
offspring. The addition of the methoxy-methylated derivative of roll-
iniastatin-2 caused less nutritional effects than its acetylated counter-
part (Ruiz Hidalgo et al., 2018).
For this reason, a candidate compound for the control of this pest
should preferably produce larval mortality. In agreement with previous
work (Tolosa et al., 2012), this report highlights rolliniastatin-2 as the
most promising compound for Spodoptera frugiperda Smith larvae con-
trol.
A relationship between the number and arrangement of THF groups,
the chemical nature of the terminal lactonic groups and the biological
activity of ACG could be inferred. Adjacent bis THF arrangement seems
to achieve the most insecticidal action.
Moreover, the hydroxyl groups flanking THF have been suggested to
be of great influence on biological activity. This becomes clear when it
is observed how the toxicity of these compounds decreases when these
groups are blocked by acetylation or methoxy-methylation reactions (Di
Toto Blessing et al., 2010). Natural ACGs were the most promising
compounds for S. frugiperda Smith larvae control.
Since hydroxyl groups flanking the THF have been blocked in MOM
and acetylated derivatives, a decrease in insecticidal activity is ob-
served. This highlights the importance of the hydroxyl group for the
insecticidal activity of natural ACG.
New control methods are necessary for crop pest management
programs due to the widespread problems of insecticide-resistant po-
pulations and the increasing consumers’ concern regarding pesticide
residues in food products. Thus, Tolosa et al. (2014) evaluated the
bioactivity of the ACG, squamocin, isolated from Annona cherimolia
Mill. (Annonaceae) and the ACG fraction of the methanol extract of
Rollinia occidentalis R. E. Fr. seeds against S. frugiperda Smith, which is a
A. Neske, et al.
primary insect pest of corn.
Seeds are particularly a promising source of ACG that can be used as
a prototype model and/or a biorational insecticide for the control of S.
frugiperda Smith. The commercial insecticides lufenuron (LUF) and
cypermetrin (CYP) (250 μg/mL) were used as positive controls. This is
the first report on the treatments mentioned on soybean and corn pests
in a field assay.
A treatment based on the ACGs fraction of methanol extract of R.
occidentalis R. E. Fr. seeds was applied to soybean crops for three con-
secutive years. In relation to the control population, the treatment re-
duced the population of Anticarsia gemmatalis Hübner, Rachiplusia nu
Gunee, Pseudoplusia includes Walker, Loxostege bifidalis F. and
Spodoptera frugiperda Smith to 52% and 65% after 48 h of application at
concentrations of 500 and 750 μg/mL respectively, while low toxic
effects were detected on natural enemies. The extract treatment at
500 μg/mL and a solution of the ACG, squamocin, at 50 and 100 μg/mL,
were also applied to a corn field to produce 75%, 93% and 100%
mortality rates on the population of S. frugiperda Smith, respectively,
after 72 h of application. In addition, damages caused by lepidopterans
in treated crops were lower than those observed in non-treated fields,
and were evaluated by residual biomass. This statement is based on
data from trials with the commercially available insecticides lufenuron
and cypermethrin (Tolosa et al., 2014).
Further specific studies, however, are needed on the impact this
compound could have on other beneficial species in agroecosystems.
Biological activity of ACG has been scarcely studied in vivo; therefore,
further tests are required to verify the potential of these compounds in
real scenarios.
6. Summary and perspectives
Annonaceous acetogenins are a relatively new class of bioactive
naturally occurring products. The difficulty of isolating these com-
pounds and elucidating their structures makes them a challenging
target for total synthesis. Their wide spectrum of biological properties is
probably the most intriguing and exciting domain, and the future will
show whether it is possible to disclose the structure-activity relation-
ship, probably on the basis of synthetic derivatives. Furthermore, it
would be useful to look for simplifications of the structure without loss
of activity.
In the last time, a great research effort has been devoted to finding
new suitable compounds to be used as corrosion inhibitors for carbon
steel in acidic solutions. These studies showed that there is a large
number of organic and inorganic compounds which, added in small
amounts to the corrosive media, can effectively decrease corrosion rate
(El-Shafei et al., 2001; Sapre et al., 2003; Wahdan et al., 2002). Many
works were conducted to assess some naturally occurring substances as
corrosion inhibitors for different metals in various environments
(Aramaki, 2001; Ein-Eli et al., 2003; Gonçalves et al., 2002; Villamil
et al., 2002; Wang et al., 2003), as well as crude extracts and pure
components isolated from the extracts (Garai et al., 2012; Kamal and
Sethuraman, 2012; Li et al., 2014; Odewunmi et al., 2015; Ostovari
et al., 2009).
Alvarez et al. (2018), gave proof of the concept of the use of Rollinia
occidentalis R. E. Fr. extract as a green corrosion inhibitor for mild steel
corrosion. This advance, i.e. its potential application, is provided by this
work for the first time in the literature. Moreover, the action of two
pure components present in the extract, namely, the acetogenins roll-
iniastatin-1 and motrilin, were also successfully tested. Results suggest
that:
(1) R. occidentalis R. E. Fr. extract can be used without further addition
of other compounds as an effective inhibitor for mild steel corro-
sion, even at very low concentrations. An increase in temperature
causes a decrease in the inhibition effectiveness.
(2) Corrosion inhibition is mainly achieved through physical
35
Phytochemistry 174 (2020) 112332
adsorption of different compounds in the extract onto the mild steel
surface.
(3) The extract of R. occidentalis R. E. Fr. can be considered a mixed-
type inhibitor since it affects both anodic and cathodic reactions.
Moreover, this behavior can be understood in terms of an inhibition
mode resulting from the geometric blocking of the metallic surface
by the adsorbed inhibitive species.
(4) Spectroscopic analyses by using the IR and UV spectra support the
coordination of O atoms to the Fe2+ ions forming complexes that
become adsorbed on the steel surface.
The ACG motrilin was reported by Alvarez et al. (2018) as corrosion
inhibitors for carbon steel in acidic solutions. The different activities
that motrilin presents constitute a very significant reason to study their
structural, electronic, topological and vibrational properties due to the
fact that they have not been reported so far. They recorded the ex-
perimental FT-IR and FT-Raman in the solid state while the experi-
mental UV-V spectra of motrilin was obtained in methanol solution, and
these spectra were not reported; only an experimental IR study related
to interactions of some ACGs with artificial lipid bilayers was published
(Bombasaro et al., 2011). These studies in motrilin are of interest to
understand why this ACG presents different properties taking into ac-
count that motrilin is a potential corrosion inhibitor for carbon steel in
acidic solutions (Alvarez et al., 2018). In this context, the research team
proposed: (i) to optimize theoretically the structure of motrilin in the
gas phase and in a methanol solution in order to calculate atomic
charges, molecular electrostatic potentials, bond orders, donor-acceptor
interaction energies and topological properties, (ii) to predict its vi-
brational spectra in both media and perform the assignments of the
main bands observed in the corresponding experimental ones, (iii) to
predict the reactivity and behavior of motrilin by using frontier orbitals
and some global descriptors and, finally, (iv) to compare their proper-
ties with those of other molecules that contain similar furan rings,
lactone, OH and CH2 groups (Bichara et al., 2010; Chain et al., 2017,
2014, 2016).
The predicted IR, Raman and UV–visible spectra have evidenced
reasonable concordance with the corresponding experimental ones.
Studies support the high stability of motrilin, especially in a methanol
solution probably due to a solute-solvent association phenomenon and
a higher reactivity in a methanol solution.
Declaration of competing interest
The authors have declared no conflict of interest.
Acknowledgments
This work was funded by the Research Council of the National
University of Tucuman (PIUNT D638) and The National Council of
Scientific and Technical Research (Fellowship)
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José Ruiz Hidalgo received his PhD degree from the
Universidad Nacional de Tucumán-Facultad de Bioquímica,
Química y Farmacia (2019) under the guidance of Professor
Adriana Neske. His main interests concern the chemistry
and biological properties of natural products.
Nuria Cabedo received her PhD degree from the
Universidad de Valencia-Facultad de Farmacia (2000). She
has done postdoctoral stays in the IRCOF of Rouen
(France), CERMN of Caen (France) and Chemistry
Department of Manchester University (UK), as well as
CEQA-IAM of Universidad Politecnica de Valencia. In 2016,
she joined the Biochemical Research Institute INCLIVA in
Valencia as postdoctoral Miguel Servet. Her research in-
terests include natural products and synthetic analogues in
the field of the medicinal chemistry focused mainly in
cardiometabolic disorders and neurological diseases. She is
author of 48 publications and 2 patents in the field.
Diego Cortes received two PhD degrees, one from the
Universidad de Valencia-Facultad de Farmacia (1980) and
another from the Universite' Paris-Sud with Professor
Andre' Cave (1985). After accepting a professorship at the
Universite' de Rouen (1988–1993), he joined the
Universidad de Valencia in 1993 where he is currently
Professor (Catedratico). His scientific interests are the dis-
covery of new natural products, their synthesis and their
biological properties. He is author of 140 publications and 3
patents in the field.

Adriana Neske obtained her PhD degree from the

Universidad Nacional de Tucumán-Facultad de Bioquímica,
Química y Farmacia (2006) under the guidance of Professor
César Catalán. She is since 2011 Associate Professor of
Organic Chemistry, in Facultad de Bioquímica, Química y
Farmacia. Her research interests are in natural products
(isolation, structure determination and biological proper-
ties).

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