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J. Nat. Prod. 1999, 62, 504-540

Invited Review
Annonaceous Acetogenins: Recent Progress
Feras Q. Alali, Xiao-Xi Liu, and Jerry L. McLaughlin*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907 Received September 18, 1998

The Annonaceous acetogenins are promising new antitumor and pesticidal agents that are found only in the plant family Annonaceae. Chemically, they are derivatives of long-chain fatty acids. Biologically, they exhibit their potent bioactivities through depletion of ATP levels via inhibiting complex I of mitochondria and inhibiting the NADH oxidase of plasma membranes of tumor cells. Thus, they thwart ATP-driven resistance mechanisms. This review presents the progress made in the chemistry, biology, and development of these compounds since December 1995. The Annonaceae (custard-apple family), considering its large size (130 genera and 2300 species), is chemically one of the least known of the tropical plant families.1 Phytochemical studies and, to a lesser extent, pharmacological studies on Annonaceous species have intensified in the last 15 years; this is largely due to the discovery of the Annonaceous acetogenins, a class of natural compounds with a wide variety of biological activities.2-6 Before 1982, most investigations centered upon the many isoquinoline alkaloids in this family. About 320 secondary natural products from 150 species belonging to 41 genera were summarized from 288 publications in 1982 by the group of Professor Andre Cave in France.1 The discovery of ´ ´ uvaricin in 1982,7 the first of the Annonaceous acetogenins, as an in vivo active antileukemic (P-388) agent, invigorated wide interest in this family. The Annonaceous acetogenins are now one of the most rapidly growing classes of new natural products and offer exciting anthelminitic, in vivo and cytotoxic antitumor, antimalarial, antimicrobial, antiprotozoal, and pesticidal activities and special promise of becoming new chemotypes for antitumor and pesticidal agents. Structurally, the Annonaceous acetogenins are a series of C-35/C-37 natural products derived from C-32/C-34 fatty acids that are combined with a 2-propanol unit. They are usually characterized by a long aliphatic chain bearing a terminal methyl-substituted R,β-unsaturated γ-lactone ring (sometimes rearranged to a ketolactone), with one, two, or three tetrahydrofuran (THF) rings located along the hydrocarbon chain and a number of oxygenated moieties (hydroxyls, acetoxyls, ketones, epoxides) and/or double bonds being present. To a lesser extent, tetrahydropyran (THP) ring compounds and acyclic compounds are also found.8-12 The Annonaceous acetogenins are the most powerful of the known inhibitors of complex I (NADH: ubiquinone oxidoreductase) in mammalian and insect mitochondrial electron transport systems;13-16 in addition, they are potent inhibitors of NADH oxidase of the plasma membranes of cancer cells;17 these actions decrease oxidative, as well as, cytosolic ATP production. The consequence
* To whom correspondence should be addressed. Tel: (765) 494-1455. Fax: (765) 494-1414. E-mail: jac@pharmacy.purdue.edu.

of such ATP deprivation is apoptosis (programmed cell death).18 Recently, we have shown that the acetogenins also inhibit cancer cells that are multidrug resistant (MDR),19-21 and in addition, they combat pesticide-resistant German cockroaches effectively.22 Thus, they thwart biological resistance. Since publishing our last four reviews,3-6 which summarized research on the Annonaceous acetogenins through December 1995, 10 new species of Annonaceae have been reported to contain acetogenins; they are Annona glabra,23-26 A. jahnii,12 A. spinescens,27,28 A. nutans,29 A. crassiflora,30 Goniothalamus donnaiensis,31-34 G. gardneri, 35 Uvaria microcarpa,36 U. pauci-ovulata,37 and Disepalum anomalum.38 In our last review, we reported the isolation of mucocin,8 the first acetogenin containing a tetrahyropyran (THP) ring nonadjacent to a THF ring. The isolations of four more THP-bearing acetogenins have now been reported; these are muconin,9 which contains a nonhydroxylated THP ring adjacent to another THF ring, pyranicin and pyragonicin,10 the first mono-THP ring acetogenins with no THF rings at all, and jimenezin,11 containing a hydroxylated THP ring adjacent to a THF ring. Also newly discovered are the first hydroxylated-THF ring compounds mucoxin,9 goniotriocin,39 and donnaienin.33 Coriaheptocins A and B, the first heptahydroxylated acetogenins, were isolated from the roots of Annona coriacea by the group of Cave;40 we have found a nonring ´ octahydroxylated acetogenin (unpublished), as confirmed by 13C NMR, CIMS, and acetylation, but we have had difficulty in locating the positions of these hydroxyls along the aliphatic chains. Recently, Cave’s group has also found ´ several important biogenetic precursors containing two to three double bonds each separated by two carbon units.29 This evidence strongly suggests that the acetogenins are actually lacceroic (C-32) and ghedoic acid (C-34) derivatives.29 A new compound, spinencin,27 is the first bis-adjacent THF acetogenin to have the relative stereochemistry (going from lower to higher numbered positions across the rings) of threo-trans-threo-cis-erythro. Jiang et al. have isolated several C-34 epimeric pairs of acetogenins from Goniothalamus donnainesis, adding a new subtype to the γ-lac-

10.1021/np980406d CCC: $18.00

© 1999 American Chemical Society and American Society of Pharmacognosy Published on Web 03/04/1999

Invited Review

Journal of Natural Products, 1999, Vol. 62, No. 3 505

tone ring configuration.31,23 The method of countercurrent chromatography is now being used to separate known and new acetogenins.41,42 The emergence of the Annonaceous acetogenins as potential agents to thwart biological resistance was first manifested in the work of Oberlies et al.19-21 in tumor cells and in the work of Alali et al.22 in insects; it was found that the acetogenins could effectively combat multidrug resistant cancer cells and pesticide-resistant cockroaches, respectively. The work of Shimada et al.43,44 on the placement of acetogenins, representing several structural classes, within liposomal membranes, now provides a new hypothesis as to how these compounds interact with lipid bilayers to exert their activity on membrane-bound enzymes. Additionally, in cooperation with a group in Japan, our recent work on the structure-activity relationships (SAR) in the isolated submitochondrial particles and work with computer models drastically challenge our understanding of the relevance of the relative stereochemistry across the THF rings.45 In our first review in 1990, 28 Annonaceous acetogenins isolated from 11 species were described; in our second review in 1993, 61 acetogenins isolated from 16 species were summarized; in our third review in 1995, another 80 acetogenins from 20 species of Annonaceous acetogenins were reported; and in our fourth review in 1996, 76 new acetogenins from 26 species were tabulated.3-6 In this review, which covers scientific progress made in the biology, chemistry, and development of Annonaceous acetogenins from December 1995 to July 1998, data have been compiled on 137 new acetogenins from 24 species (Appendix 1). At the time of preparation (August 1998) of this current review, over 350 Annonaceous acetogenins have been isolated from 37 species. Our preliminary efforts show that about 50%, of over 80 Annonaceous species screened, are significantly bioactive and are worthy of fractionation; thus, this class of compounds can be expected to continue to grow, at an exponential rate in the future, provided that financial support for such research efforts can be found. With the demise of the world’s tropical rain forests, such work is compelling before the great chemical diversity, contained within these endangered species, is lost. Classification In our last review,3 the Annonaceous acetogenins were classified according to their relative stereostructures across the THF rings; while that classification is more informative than any other method, it leads to a plethora of subclasses, and we will use herein our earlier system of classification with some additions and modifications. The Annonaceous acetogenins seem to be best classified into mono-THF, adjacent bis-THF, nonadjacent bis-THF, non-THF ring, triTHF, and nonclassical acetogenins (THP and ring-hydroxylated THF compounds), followed by subclassification of the γ-lactone, substituted γ-lactone, or ketolactone variations (Figure 1). The names, classfications, chemical and biological data, and references to the new compounds, reported December 1995-July 1998, are tabulated in Appendix 1. Biogenesis Biogenetically, the Annonaceous acetogenins seem to be derived from the polyketide pathway. The THF, THP, and epoxide rings are suggested to arise from isolated double bonds through epoxidation and cyclization.3,4 The discovery of earlier precursors (nonring compounds, epoxides, ketones, diols, and double bonds), the location of double bonds

Figure 1. Core units for classification of Annonaceous acetogenins.

in the appropriate positions, and the semisynthesis of additional THF rings from double bond-containing acetogenins strongly support this hypothesis. The discoveries of muridienins, proposed precursors of the mono-THF acetogenins, and chatenaytrienins, proposed precursors of the bis-THF acetogenins, add new evidence that acetogenins are more likely to be derived from lacceroic (C-32) and ghedoic (C-34) fatty acids after enzymatic combination with a three-carbon unit.29 We could not find these free acids or their esterified products in the oily extracts of the paw paw, Asimina triloba; this might suggest that these free acids actually serve as short-lived intermediates in the biosynthetic process and are shuffled along complex enzyme subunits rather than being released as end products that can later be metabolized by γ-lactone formation, dehydrogenation, epoxidation, and cyclization. The sequence of these events is still unknown. The time is at hand to conduct feeding experiments with isotopically labeled precursors to verify the biogenetic pathways and the sequence of events leading to these compounds. Plant tissue culture methods have not yet produced sufficient cell growth to permit such studies. One wonders why the plants in this family choose to biosynthesize more than 350 different acetogenins, with all of them being either C-32 or C-34 fatty acid derivatives, and not produce C-36 or C-38 or even C-30 or C-28 compounds. The dimensions of cell and mitochondrial membranes43 (the sites of the target enzymes) may dictate this; this particular chain length has likely evolved because it provides the optimum activity and protection of the plant against herbivores and pests. Shorter acetogenins lose activity, and it may be logical to assume that longer ones will also be less active. The biogenetic story of goniocin is particularly interesting. This tri-THF ring acetogenin was first isolated in our laboratory by Gu et al. in 1994 from Goniothalamus giganteus.46 All previously isolated acetogenins from this plant, representing over 30 different compounds,47 had an R configuration at C-10 including cyclogoniodenin T,48 a semisynthetic tri-THF enantiomer of goniocin; however,

506 Journal of Natural Products, 1999, Vol. 62, No. 3

Invited Review

Figure 2. Biogenetic schemes for goniocin and cyclogoniodenin T.

using NMR-derived information, goniocin was assigned an S absolute stereocenter at C-10. This means that goniocin and cyclogoniodenin T have to be epimeric at each of the seven chiral centers across the tri-THF ring system. The absolute stereochemistries of all of these compounds had been determined using Mosher ester methodology.49 To help verify this remarkable coexistence of these naturally multicentered enantiomers, Sinha et al. at Scripps50,51 totally synthesized both compounds and confirmed that their absolute configurations were, indeed, correct as proposed. They relied upon the subtle differences of the chemical shifts of the methoxy group of the Mosher ester derivatives of both compounds and comparison with the original spectra of goniocin.46,50,51 They interpreted this unique coexistence to be a result of two alternative modes of tandem ring-closure routes, both starting with epimeric 10-hydroxy intermediates (Figure 2).51 Extraction, Isolation, and Purification The Annonaceous acetogenins are readily soluble in most organic solvents. Ethanol extraction of the dried plant material followed by solvent partitions, to concentrate the compounds, is still the method of choice in our laboratory.4 Two methods are in use to monitor the fractionation, which is mainly achieved by open column chromatography; these are bioactivity-guided fractionation using the brine shrimp lethality test (BST)52,53 and/or TLC spot visualization using Kedde’s reagent.4 Kedde’s reagent is not specific for the acetogenins; it detects the unsaturated conjugated lactones and does not detect the translactonized ketolactones; thus, the BST is superior in guiding fractionation and quickly leads to the most bioactive compounds. After open column chromatography, HPLC is then the most efficient method to purify individual compounds from the complex mixtures of the closely related acetogenins. Reversed-phase C18 HPLC is superior to silica gel normal-phase HPLC in achieving separation of single-positional epimeric pairs, diastereomeric acetogenins, and/or closely related isomers. Countercurrent chromatography (CCC) has now been used for the first time in isolating Annonaceous acetogenins; this was demonstrated by the independent work of Duret et al.41 and Hopp et al.42 While Duret et al. were the first to use the technique, Hopp et al. were the first to isolate new compounds using CCC. Duret et al. have used a biphasic mixture of heptane/ethyl acetate/methanol/water to isolate four pairs of acetogenins, which were then

purified with HPLC. Hopp et al. developed a biphasic system, hexane/dichloromethane and methanol/water (10: 5:7:3), because it yielded nearly identical bioactivity in the two phases. Using the BST, after a sample of the bioactive fraction F005 had been partitioned between the two phases, Hopp et al. were able to isolate quickly four known and three new acetogenins; the last purification step was achieved by HPLC. CCC could be utilized to provide adequate amounts for further testing the major compounds from the crude extracts, in relatively short time. By far, the major contribution to the detection, isolation, characterization, and dereplication of Annonaceous acetogenins in the last two years has come through the application of liquid chromatography-electrospray ionization mass spectrometry (LC/EIMS) techniques.54,55 Using the positive-ion mode and under conditions of atmospheric pressure in-source collision-induced dissociation (APICID), the acetogenins have provided reproducibly characteristic ion patterns and fragment ions.54 Analyzing the selected ion chromatograms (SIC), the presence of these acetogenins and other derivatives in crude plant extracts and chromatographic fractions can be readily detected. Utilizing the LC/(+)ESI-APCID-MS technique, acetogenins produce characteristic ion patterns consisting of [M + Na]+ and [M + H]+ molecular ions, as well as ions showing the consecutive losses of H2O from the [M + H]+ ion. LC/MS screening of a 2 µg aliquot of a bioactive crude methanol-soluble fraction of Rollinia mucosa detected the presence of some 40 known acetogenins in this plant species, in addition to four new acetogenins of diverse structure.54 As an example of the utility of this method, Gu et al. then applied the LC/(+)ESI-MS method to direct the isolation of two of the new compounds.55 In another study which evaluated the monthly variations of acetogenin content in crude CH2Cl2 extracts of twigs collected from a single paw paw (A. triloba) tree, Gu et al. used the LC/MS/MS technique to quantify the contents of the three most biologically potent acetogenins.56 The quantified contents of these acetogenins showed good correlation with potencies as observed in the BST and demonstrated the highest activities in extracts from the May and June samples. These results clearly demonstrated seasonal variations in acetogenin content and suggest that May and June are the best time to collect paw paw twigs for maximizing bioactivities. Most recently, these methods have confirmed that the BST-active extracts of the zebra swallowtail (Eurytides marcellus) butterflies and larvae, which are obligate parasites on the paw paw leaves, contain the potent acetogenins bullatacin, bullatalicin, trilobacin, and/or asimicin.57 This well-defined LC/MS/MS method will undoubtedly be widely applied in the quantitative analysis of other desirable natural components in crude extracts in the future. Structural Elucidation Synthetic models of known stereochemistry are used routinely to predict the relative stereochemistry of both the THF and the γ-lactone ring systems bearing the nearby 4-hydroxyl of the acetogenins.58-62 The locations of the THF ring and/or the free hydroxyls continue to be determined by careful analysis of mass spectral fragments.2-4 No significant changes have been introduced in the methods for structural elucidation of Annonaceous acetogenins in the last two years. Nevertheless, the following three contributions merit discussion. Duret et al. have noticed that the non-4-hydroxylated γ-lactone moiety of the Annonaceous acetogenins may be

and tonkinesin B all have a pseudothreo relationship between their carbinol centers at C-15 and C-17. it can be predicted that tonkinin A. sugars) or some asymmetric reactions using chiral catalysts (Sharpless epoxidation. basic conditions must be avoided in extraction.9-cyclododecatriene. and definite stereochemical assignments are not easily made. obtained by the cleavage of the terminal R.88 The implications of their work will be discussed in the following section dealing with mechanism of action. in the long aliphatic chain.32 ppm in the 1H NMR spectrum and an upfield chemical shift of ca. determination of the specific rotation of the mixtures and enzymatic oxidation after chemical degradation. In comparison with an isolated hydroxyl oxymethine along a hydrocarbon chain. possess the S absolute configuration at their C-36 or C-34 positions. selectivity. have been proven to be very helpful in predicting the relative stereochemistry of the THF ring systems.77 Towne and McDonald. in the last two years. and they completed the synthesis in 20 steps. also. using tandem cyclization with rhenium oxide. fractionation. successfully synthesized goniocin46 and cyclogoniodenin T48 and its unique tri-THF stereoisomer. 1.79 Ruan et al. in 1982. hydroxyl oxymethines of 1.2-4. uvaricin.64 To date.73 Utilizing γ.78 Figadere et al. comparison by circular dichroism is used.92 (+)-squamostanal-A.4 thus. 1H and 13C NMR.β-unsaturated γ-methyl-γlactone.70 This work confirmed our proposed relative as well as absolute stereochemistry of mucocin and... +0. Shi et al.91 (+)-squamocin K.81 Gesson et al. this suggests that the C-4 hydroxyl and the THF flanking hydroxyls may be involved in some electron-donating hydrogen-bonding interactions at the target site or in the membranes.90 4-deoxygigantecin (the first bis nonadjacent THF acetogenin to be synthesized)..67-69 Convergent strategies are usually chosen to synthesize these compounds. with more than 350 acetogenins isolated.71 in facilitating the absolute stereochemical assignments of closely located carbinol centers. X-ray crystallography is difficult. and isolation to preserve the natural integrity of the γ-lactone.51 Inspired by Hoye’s work. Kienan et al.65 This method uses only small amounts of material that are sufficient to achieve the per-Mosher esters. 1999.18-bis-epi-goniocin. the first THP-bearing acetogenin.3. HPLC detection of NADH released from the enzymatic oxidation of L.3-diols. and UV spectra. and the reader is encouraged to consult the original papers. they were able to synthesize (+)-asimicin. tri-THF compounds. This can be seen in the work of Sasaki et al. On the other hand. and (+)-parviflorin.86 The semisynthetic work of Ye et al.8 ppm in the 13C NMR spectrum. A noteworthy strategy is the efficient bidirectional synthetic approach to the C-2 symmetric stereoisomers of 2. it was obvious that synthetic models were urgently needed to aid the complete structural elucidations of these multi-stereocentered compounds. Kienan et al. They observed that the cancellation/enforcement effect of overlapping MPTA planes could still be analyzed and utilized to predict the absolute stereochemistry of the 1.g. except when so epimerized. combinatorial chemistry has been applied in this field.or γ-oxygenated allylic stannane. have successfully applied the Mosher ester method to determine the absolute stereochemistry at 1.94 The methods employed are diverse.2′-bis-THF acetogenins as reported by Marshall et al.62 Additional synthetic models are still needed to predict the relative stereochemistry of several of the expanding new types of acetogenins.7 Several synthetic models... and the bis-THF compounds with one flanking hydroxyl. Since the discovery of the first acetogenin.3-pseudothreo diols usually experience downfield shifts ca. No. 62.59 in being able to predict the relative stereochemistry of the hydroxyl-flanked THP ring as well as the hydroxyl-flanked THF ring. using all-trans-1.2vicinal diols. respectively. +0.γ′-dioxygenated dialdehyde and a nonracemic R. and of the 4-hydroxylated γ-lactone. have allowed characterization of these epimers.84 Zhang et al. all of the natural Annonaceous acetogenins. the hydroxylated-THP compounds. especially those that do not require derivatization. We anticipate that nitrogen or sulfur derivatives might enhance or modify the activity. tonkinin B. Demonstrated targets were previously discussed as the reduced nicotinamide adenine dinucleotide . (+)-5S-hydroxyparviflorin. and/or the potency of acetogenins.5.75 While it is not as efficient. either chiral starting materials (R-amino acids.10. The potent and diverse bioactivities of Annonaceous acetogenins have recently caught the eye of many groups of synthetic chemists. 3 507 epimerized upon treatment with weak base.10 A pseudothreo or -erythro spatial relationship can be easily deduced by analyzing the 1H and 13C NMR chemical shift differences of the carbinol centers in comparison with an isolated hydroxyl group at a carbinol center in a long chain. which was published without any stereochemical assignments of its seven stereocenters. they have now modified this method and extended it to the synthesis of the bis-THF acetogenins with asymmetrical cores. Sasaki et al. The following compounds have also been recently synthesized: longifolicin.93 and (8′R)and (8′S)-corossoline.32 ppm and ca.Invited Review Journal of Natural Products. and asiminecin.50 ppm in both the 1H and 13C NMR spectra. To achieve the specific stereochemistry.89 15-epi-annonin I.83 Seepersaud et al. Alali et al. Sharpless dihydroxylation) are employed..58-60. These are based on the coupling of a THF ring core and a terminal γ-lactone synthon.63 The two resulting C-36/C-34 epimers have identical MS. also synthesized mucocin.80 Li ` et al. Mechanism of Action The acetogenins are known to be very potent cytotoxic compounds.85 and Zanardi et al. Accordingly. However.82 Koret et al. with their flanking hydroxyls..87 has shown that certain chlorinated derivatives of the natural acetogenins lose activity. and these models could be logical targets for further syntheses. have synthesized several bullatacin analogues in order to test their metal-binding ability. have tabulated interesting observations on the chemical shift differences of 1. As demonstrated by their total synthesis of trilobacin.. and to the intramolecular formaldehyde closure reaction. tonkinesin A. -2. added credibility both to Born’s rule. asiminocin. assuming that MPTA groups could still freely rotate. 17.or D-lactic acid. +0.2-vicinal diol compounds.72 Thus. and preserve their ideal conformations.74.66 Synthesis Due to the waxy nature of the Annonaceous acetogenins. Kienan et al. to pyruvic acid by lactate dehydrogenase was used to quantify the epimerization chemically.. Vol. designed an efficient convergent synthetic strategy that provided a useful entry to a 32-membered chemical library of stereoisomeric bis-THF acetogenins. e. To determine the absolute stereochemistry at the C-36 or C-34 centers of such Annonaceous acetogenins.3-pseudoerythro diols usually experience a downfield chemical shift of ca. IR.50.76 Several elegant attempts have been directed toward the synthesis of core synthons that could be utilized to produce biologically active natural and nonnatural analogues of the acetogenins.

22 Landolt et al. (7) A ketone instead of a hydroxyl functional group decreases the activity. most Annonaceous acetogenins (except rolliniastatin-2 and cherimolin-1) and rotenone were found to be mutually exclusive inhibitors. and insects.96 the following generalizations can be stated concerning the SARs of the Annonaceous acetogenins: (1) The bis-adjacentTHF acetogenins are the most potent among this family.136 Third. however.e.17 Annonaceous acetogenins are now considered as the most potent.95 and Delgi Espositi et al. In their recent SAR study of Annonaceous acetogenins in purified rat liver mitochondria. while both rotenone and the Annonaceous acetogenins do bind noncompetitively against exogenous ubiquinone at complex I..99 and Delgi Esposti et al. (4) The spacer. e. and DMPC-Mn2+ peak-broadening studies. Regardless of their future utility as chemotherapeutic. First.97 Alali et al. Thus. 1999. the lactone ring.96 where Annonaceous acetogenins were concluded to bind competitively with respect to the ubiquinone at complex I. in turn. Studying the conformations of the Annonaceous acetogenins within liposomes made of dimyristoylphosphatidylcholine (DMPC) and on the basis of 1H NMR intermolecular nuclear Overhauser effects (NOEs).122. containing either mono-. Implementation of COMPASS (COMmon geometrical Pattern Search System) and molecular field fitting for all combinations of the stable conformations of each molecule. the same resarchers studied Ca2+ and Mg2+ complexation of acetogenins in organic solvents. i. noted that the activity of the nonadjacent bis-THF ring acetogenins depends on the distance between the two THF rings.97-99 While the acetogenins are not ionophoric in living cells. in general but not always.. i. etc. as Miyoshi et al. this was corroborated by an exhaustive conformational space search analysis that indicated that the model compounds.16. (8) Ketolactone acetogenins are still active but usually less active and more selective than their parent compounds. tethered to spacer moieties of different lengths. useful tools. agents.. the stereochemical differences within the THF rings of the acetogenins should not make much difference in their bioactivity profiles. the shorter C-35 acetogenins are more potent than the C-37 compounds. (9) The THP ring compounds are as active as the THF compounds and have the same mechanisms of action.100 several investigators have studied the ion complexation ability of the Annonaceous acetogenins.44 and Miyoshi et al. in this work led to several important conclusions.45 Oberlies et al. in the proven protein target.2. may contribute to their activity. they have different binding sites. that complexation with the Fe-S cluster. like the findings of Gonzalez et al.. to probe the biochemistry of these active sities.96. and beyond the tetra-hydroxylated acetogenins the activity drops drastically.98 Gu et al. stated. 3 Invited Review (NADH): ubiquinone oxidoreductase in complex I.71 Alfonso et al. is critical to the potency and selectivity of the acetogenins. (2) The R.43. Vol. drastically challenge our understanding of the significance of the relative and absolute stereochemistries of the THF or THP ring systems. respectively. Fourth. with little justification.22.3. (5) Neither the 4-OH group nor the 10-OH group is essential for activity. mitochondrial NADH ubiquinone oxidoreductase and plasma membrane NADH oxidase. the distance between the OH-flanked THF and the γ-lactone. This work is in good agreement with the earlier results obtained by Shimada et al.. Structural-Activity Relationships On the basis of the recent work of Miyoshi et al. and adapts to the geometry of specific cell types. (3) If all other structural features are identical. differential calormetric scanning data. they may have different space group distances for optimal activity than their parent compounds. the inhibition mechanism of Annonaceous acetogenins was found to be noncompetitive against exogenous ubiquinones.101 There is no evidence that Ca2+ or Mg2+ complexation contribute to the potent cytotoxic or pesticidal activities of these compounds.21.g..99 Alfonso et al.71.45 They also studied the three-dimensional structure of the bis-THF ring moieties of the different possible stereoisomers optimized by quantum chemical calculations (MNDO-AM1). yet. superior to the mono-THF compounds. were essential for potent activity.44 and with several of our earlier SAR studies in isolated mitochondrial whole cells. among the diverse inhibitors of mitochondrial complex I.43. adjacent bis-. Investigations of Fe2+and FeS-acetogenin complexation in aqueous media are suggested. which. may. which is a membrane-bound protein of the mitochondrial electron transport system13-15 and the ubiquinone-linked NADH oxidase in the plasma membranes of cancerous cells. provide both the optimal position and polarity needed for the most potent activity. on one hand.e.138 While no work has been conducted on the molecular inhibitory mechanisms of these compounds. Shimada et al. or nonadjacent bis-THF ring moieties.β-unsatur- ated γ-lactone ring moieties.. a 13carbon space in the OH-flanked mono.and bis-THF compounds is optimum for activity. stereochemistry surrounding the THF rings. in the future. This would seem to explain cell type selectivities as seen with several of these compounds. 62. Second. explain and verify our structure-activity relationship profiles and.4 In a study to determine the essential structural factors.. found that the Annonaceous acetogenins. have their THF ring moieties residing at the interfacial regions of the lipid membranes. It was also found that the position of the THF ring anchor along the acetogenin chain determines the depths of penetration of the lactone functional group within the lipid bilayer. effective in nanomolar concentrations.e.. the activity decreases to that of a mono-THF ring aceto- ...137 and ´ Gallardo et al. surprisingly. this conclusion is not in agreement with the results of Friedrich et al. which links the THF and the R.122.44 It was concluded that the THF group(s) serve as a hydrophilic anchor in the lipid membranes.. but this point needs further study.β-unsaturated γ-lactone at the end of the chain is crucial for activity.138 proper length and flexibility of the alkyl spacer moiety. two flanking the THF ring(s) and another somewhere in the long hydrocarbon chain. the work of Shimada et al. seems to be much less important for activity at the enzyme level than in previous bioassays.21 He et al. if the THF rings serve as an anchor at the interface of the membrane. were in fairly good superimposition.88. with different stereochemical arrangements around the THF moieties. they should become. antimicrobial. used 22 representative acetogenin compounds to conduct a mechanistic and structural activity study against submitochondrial particles. i.. acts directly with the protein receptor site(s). (6) Three hydroxyl groups. pesticidal. on the other hand. Miyoshi et al.43.45 Indeed. penetrates the lipid membrane to different depths.45 using liposomal membranes and the submitochondrial vesicle particles. The door is now open for further studies of the molecular inhibitory mechanism of Annonaceous acetogenins against their protein targets. the nonadjacent bis-THF compounds are. are more potent than the nonring THF acetogenins. Some researchers have proposed. No.508 Journal of Natural Products. at the least.

against the MCF7/wt cells. trilobacin102 and asiminocin103 have shown ED50 values of <10-12 µg/mL in several human tumor cell lines. Figure 4. showed similar effectiveness of bullatacin (67% tumor inhibition at 50 µg/kg) against X-5563 plasma cell myeloma grafts in normal mice. and bullatalicin. indeed. compounds. against MCF-7/Adr cells. bullatacin was effective at inhibiting the growth of the MDR MCF-7/Adr cells and exhibited a linear dose-response curve over a concentra- . and it is even possible that hydrogen peroxide. in general. bullatacin and (2.20. vincristine.19-22 In vitro and in vivo Cytotoxicity Results. and vinblastine against MCF-7/wt cells. Oberlies et al. A thorough examination of the acetogenins against in vivo models of multidrug resistance is now suggested. adriamycin. and vinblastine (Figures 3 and 4). whether intrinsic or acquired. While extensive and comprehensive in vivo testing has yet to be conducted. This observation led to the hypothesis that the acetogenins were cytotoxic to the MCF-7/Adr cells but more cytostatic to the MCF-7/wt cells. effective at only 50 µg/kg.104 mosin C with an ED50 of 10-4 µg/mL against pancreatic carcinoma cells (PACA2). has several interesting and potent biological activities. and vinblastine. Alternatively.. a 170 kDa transmembrane energy-dependent drug efflux pump. and bullatacin.4 mg/kg) and asimicin (124% T/C at 25 µg/kg) were active in the same assay. Yet. observed that the MCF-7/Adr cells were more susceptible to acetogenin treatment and elicited a linear dose response curve.6 It must be remembered that the murine leukemias are used as indicators of in vivo antitumor activity.105 and pyranicin with an ED50 of 10-2 µg/mL also against PACA-2. The concentration values are log dose units in µg/mL. and pesticidal effects. 1999. e. 62. Grindey at the Eli Lilly Co. Values are expressed as percentages of the vehicle-treated controls with each point representing the normalized average of four values and the error bars representing the standard deviation about each average. this class of diverse. It is not yet clear how the acetogenins can inhibit the growth of 50% of in vitro grown cancerous cells at concentrations of <10-12 µg/mL.. adriamycin. The concentration values are log dose units in µg/mL. metabolism. was over 300 times more potent than paclitaxel against L1210..2-6 Potentially of greatest importance. Effect of exposure for 6 days to the standard antineoplastic drugs. at 1 mg/kg. Uvaricin originally showed in vivo activity against 3PS (murine lymphocytic leukemia) (157% T/C at 1.4-cis and trans)-bullatacinones were tested against L1210 (murine leukemia) in normal mice and in tumor xenografts of A2780 (human ovarian carcinoma) in athymic mice. vincristine. With water-soluble derivatives in hand and with better understanding of their SAR. such as intracellular transportion. vincristine.4 Previously unpublished results. Effect of exposure for 6 days to the standard antineoplastic drugs. at 50 µg/kg. the Annonaceous acetogenins have. MDR tumors. antimalarial.7 and the rollinones (147% T/C at 1. respectively). For example.. because of their potent ability to block ATP production. It was also observed that when one THF ring is replaced with a tetrahydropyran ring (THP) the activity remains comparable. and inactivation and receptor geometry may all contribute to this phenomenon of selectivity. Some Annonaceous acetogenins may be among the most potent cytotoxic agents ever known. were almost equivalent to cis-platinum. including antibacterial.g. can selectively inhibit the growth of MDR tumors cells in vitro.Invited Review Journal of Natural Products. development of the optimum compounds into clinically useful antitumor agents should be a top priority. these agents are not “general cytotoxins” as some authorities continue to profess. in addition. Annonaceous Acetogenins vs Multidrug Resistant Cells. Stereochemical differences did not show any significant differences in potency. a plateau near the IC50 value was observed (this is commonly seen with acetogenins). obtained by the late G. the acetogenins caused much less weight loss than the standards. cytotoxic selectivities. among various cell lines. already shown promising in vivo results. induced by apoptosis and resulting radical oxygen formation. Vol. in contrast to adriamycin. Several factors.21 we showed that acetogenins. 3 509 genin if the distance is too long. parasiticidal. in the last two years the Annonaceous acetogenins have emerged as promising new leads to thwart resistance in multidrug resistant (MDR) tumors and in pesticide-resistant insects. No. In our recent work. MDR tumors are usually associated with an increased Figure 3.15 Bullatacin. Biological Activity As previously noted. squamotacin with an ED50 value of 10-8 µg/mL against the human prostate cell line (PC-3). but still closely related. Values are expressed as percentages of the vehicle-treated controls with each point representing the normalized average of four values and the error bars representing the standard deviation about that average. At the Upjohn Co. and are not just predictors for antileukemic agents. in vivo antitumor.19 Thus. e.10 A series of acetogenins all show greater cytotoxic effects to cancerous vs noncancerous cells. continue to limit the life span of cancer patients in remission. have been observed concurrently. diffuses into neighboring cells where it is lethal.g. expression of P-glycoprotein. Using both wild-type and adriamycin-resistant human mammary adenocarcinoma cells in vitro (MCF-7/wt and MCF-7/Adr.4 mg/kg).

e. At the most concentrated dose of 1. the cell growth of the parental MCF-7/wt cells was only inhibited by 50%. Values are expressed as average absorbances (n ) 6 for the vehicle treated control. there was the usual plateau near the IC50 value against the parental MCF-7/ wt cells.0 µg/mL.0 µg/mL of adriamycin.0 µg/mL) was cytotoxic to the MDR MCF-7/Adr cells since these cells would not regrow after being fed with fresh media (Figure 8). the MCF-7/Adr cells were completely unaffected by the antineoplastic agent. regardless of the dose of bullatacin (Figure 7). 6. and 7). Figure 7. The concentration values are log dose units in µg/mL. using the same doses.510 Journal of Natural Products. 1999. A similar refeeding experiment. thus. n ) 4 for the bullatacin treated wells). Likewise..0 µg/mL of bullatacin against MCF-7/Adr cells with refeeding of fresh media in half of the plates. bullatacin was more cytostatic than cytotoxic to these wild-type cells (Figure 9).20 To understand better the cytotoxicity against MDR MCF7/Adr cells and to suggest the structures optimum for future synthetic and biological evaluation. Vol. a SAR study was . whereas the MCF7/wt cells were no longer viable after adriamycin treatment. nearly zero cell growth at the most concentrated dose of 1. Values are expressed as average absorbances (n ) 6 for the vehicle treated control.20 Both cell lines were then analyzed to determine if they were still viable after bullatacin treatment (Figures 8 and 9). 62. Figure 6. the MCF-7/wt cells were able to grow to a level near that of the vehicle-treated control upon being fed fresh media. and the error bars represent the standard deviation about each average. In the MDR MCF-7/Adr cells. bullatacin inhibited cell growth by varying amounts in a dose-dependent fashion. dose independent cell growth was confirmed in the MCF-7/wt cells both at the end of 6 days of bullatacin exposure (Figure 5) as well as over the 7 days of the assay (Figure 7). Periodic analysis (every 24 h) of the effects of serial dilution of bullatacin against MCF-7/wt cells. n ) 4 for the bullatacin treated wells). Figure 8. Periodic analysis (every 24 h) of the effects of serial dilution of bullatacin against MCF-7/Adr cells. Alternatively. A 48-h exposure to bullatacin (1. No. showed the opposite results. Comparison of the effects of exposure for 6 days to bullatacin against MCF-7/wt vs MCF-7/Adr cells. relative to the growth of the vehicle treated controls.0 µg/ mL vs nearly 100% cell growth at the least concentrated dose of 1. tion range of 1. Periodic analysis (every 24 h) of the effects of 1. 3 Invited Review Figure 5. and the error bars represent the standard deviation about each average.0 µg/mL to 1. Values are expressed as percentages of the vehicle-treated controls with each point representing the normalized average of four values and the error bars representing the standard deviation about each average. i.0 × 10-4 µg/mL (Figure 5). using 1.0 × 10-4 µg/mL (Figure 6). and the error bars represent the standard deviation about each average. However. Values are expressed as average absorbances (n ) 6 for both control and drug treated wells). The “R” indicates when refeeding was initiated. This observation was examined further by analyzing the growth of both cell lines periodically over the 7 days of the assay (Figures 6 and 7). bullatacin inhibited nearly all of the growth of the MDR MCF-7/Adr cells but only 50% of the growth of the MCF7/wt cells (Figure 5). A linear dose-response curve in the MCF-7/Adr cells after a 6-day treatment (Figure 5) reflects dose dependent cell growth when analyzed on a daily basis (Figures 4. The concentration values are log dose units in µg/mL. However. The concentration values are log dose units in µg/mL.

organophosphate. this might be attributed to such factors such as. all previous studies.21 The most potent compound. and vincristine against multidrug-resistant MCF-7/Adr cells. thus. 1999. carbamate. but we have not evaluated the original data (personal communication). two bis-nonadjacent. germanica nymphs of both strains to this variety of the acetogenins and to the five conventional synthetic insecticides. annomontacin).15. 62. While Oberlies et al. nymphal development was mainly affected by gigantetrocin A and bullatalicin. Thirteen of the 14 acetogenins were generally more potent than all three of the standard drugs. Periodic analysis (every 24 h) of the effects of 1.22 Most of these insecticides interfere with the proper functioning of the cockroach nervous system or other physiological processes after entering the body following direct contact. carbamate (propoxur. second and fifth instars. and nonadjacent bis-THF (sylvaticin. Figure 10. tests were conducted at 1000 ppm of all test compounds in the diet (bait). i. European corn borers. thus.107 On the basis of our preliminary testing (topical bioassays). The “R” indicates when refeeding was initiated. but not restricted to.97. As previously mentioned.106 Concurrent therapy of acetogenins with the traditional antitumor agents would. Values are expressed as average absorbances (n ) 6 for both control and drug treated wells).0 µg/mL of bullatacin against MCF-7/wt cells with refeeding of fresh media in half of the plates. Shortening the length of the alkyl chain decreased the potency significantly in this particular cell line.99 and with the purified enzyme. and pyrethroid classes of synthetic insecticides. gigantetrocin A (a mono-THF ring acetogenin). adjacent bis-THF (asimicin. spider mites.e. striped cucumber beetles. was two times as potent as bullatacin.Invited Review Journal of Natural Products. Bullatacin is 258 times more cytotoxic against MCF-7/Adr than adriamycin. and the error bars represent the standard deviation about each average. intracellular transport. representing the mono-THF (gigantetrocin A. Adriamycin has been reported to us to accumulate in bullatacin-treated MDR tumor cells.21 have observed slight differences in potency between stereoisomeric acetogenins. The acetogenins caused high percentages of mortality and delays in development of the fifth instars of both strains (Figure 11). based on cellfree systems. membrane transport. cockroaches are controlled primarily by the use of conventional synthetic insecticides that provide a relatively rapid and efficient means of reducing cockroach populations. bean leaf beetles. or ingestion.21 All compounds were tested with adriamycin. bullatalicin) classes of Annonaceous acetogenins. blowfly larvae. a resistant German cockroach strain. vinblastine. In the Jwax-susceptible German cockroach strain. nymphal development was mainly affected by gigantetrocin A and annomontacin. Comparison of the cell growth inhibition potential of bullatacin vs the standard antineoplastic compounds adriamycin.. No. bendiocarb). application as mixtures in crude extracts has been suggested. Acetogenins have been frequently described in the literature as being toxic to mosquito larvae. and vinblastine. and free-living nematodes. or metabolic inactivation in the whole cell assay systems. The concentration values are log dose units in µg/mL.22 Thus. Values are expressed as percentages of the vehicle-treated controls with each point representing the normalized average of four values and the error bars representing the standard deviation about each average.45 with the purified mitochondrial enzyme. as standard chemotherapeutic agents (Figure 10). Repeated applications of these insecticides have resulted in the development of resistance to the chlorinated hydrocarbon. The development of novel insecticide classes with new biochemical mechanisms as targets is needed to help to overcome this resistance problem. those patients who have already developed MDR would be expected to benefit substantially by acetogenin treatment. 3 511 Figure 9. and in addition.107 The acetogenins typically occur as complex mixtures of over 40 different compounds within the plant extract. Acetogenins with the stereochemistry threo-trans-threo-trans-erythro (from C-15 to C-24) were the most potent among the bis-adjacent acetogenins. Differential susceptibility occurred among B. Annonaceous Acetogenins vs Resistant and Susceptible Insects and Pests. conducted with 14 structurally diverse acetogenins (seven bis-adjacent. acetogenins are more toxic by ingestion than by contact to cockroaches. electron-transport inhibition in rat liver mitochondrial suspensions98.45 did not. organophosphate (chlorpyrifos).22 As a widespread urban insect. and five mono-THF ring compounds). parviflorin). exposure to vapor.21 The optimal length of the alkyl chain between the THF ring and the γ-lactone was 15 carbons as recently corroborated by Miyoshi et al. potentially extend patient survival times. Mexican bean beetles. whereas in Muncie. and pyrethroid (cypermethrin) insecticides to determine their dietary toxicities to insecticide-resistant and insecticidesusceptible strains of the German cockroach. vincristine. Six compounds. which are better mimics of in vivo effects. melon aphids. were compared with technical grades of synthetic amidinohydrazone (hydramethylnon). permitted ranking of all 11 compounds. . The adjacent bis-THF acetogenins showed the highest potency among the three acetogenin classes (Tables 1 and 2). Vol. Blattella germanica. The speed of killing values (LT50) against insecticide-susceptible (Jwax) and insecticide-resistant (Muncie). Colorado potato beetles.

2)* 1.8) 1.1)* 1.0 47. and the RR was not calculated. b There was a single response value to cypermethrin.6) 2. showed the lowest RR among the synthetic pesticides.9-2.9 3.7-1.6 0.3)* 1.9 (0. and it is predictable that such pesticide-resistance also includes ATP-dependent factors.9 (0. no lethal time was estimated.0 (0.8 2.2 3.5 2. LT50 Valuesa for German Cockroach Fifth Instars compound type natural active ingredient parviflorin asimicin sylvaticin bullatalicin annomontacin gigantetrocin A cypermethrin chlorpyrifos hydramethylnon propoxur bendiocarb Jwax (susceptible strains) 0.107 The methanolic-soluble fraction. tures of acetogenins obtained from plant extracts.6 to 8. Effects of Annonaceous acetogenins (1000 ppm in bait) on development of fifth instars of (a) the Jwax and (b) Muncie strains of Blattella germanica.4)* 0. 62.4 43.7 6. indeed.0 (4.9)* synthetic a Resistance ratios (95% confidence limits.3-2.1 4.1 3. Low resistance ratios (RRs) were obtained for most compounds (except chlorpyrifos) (Table 3). a fluidextract of paw paw seeds was once sold as an emetic by the Eli Lilly Co.8 0.22 suggested an excellent potential for the use of Annonaceous acetogenins in baits against cockroaches.8 (2.8 Muncie (resistant strain) 0.9 to 2.8 24.9 50. Whenever the 95% CL of a ratio includes 1 (values with an asterisk).2 (0.6 (1. Further research is now needed to develop more refined treatment strategies for the inclusion of effective baited formulations. gave negative results in the Ames mutagenicity test (Sitek Research Laboratories.1 7.6 6.8 (1.4 20.1) fifth instar RRa (95% CL) 1.1)* 3.0 (0.6 (0.1 2.4-2.1-9.2 6. F005.2 (1. CL) at LT 50 value estimates. Most of the acetogenins tested performed better than the conventional insecticides against both stages of both strains (Tables 1 and 2). the use of a large t value caused nonrealistic confidence limits (CL) to be calculated.8 0. Low resistance ratio values for second instars ranged from 0.5-5. unpublished results).1)* 8. 3 Table 1. no lethal time estimate was made.0 to 3.0 with the synthetic compounds (Table 3).5 (1. shown in this study.8 8.8 1.8 17. No.2 to 3. unpublished data).8 Muncie (resistant strain) 1.8 (1. nine out of 10 tests were negative on the histidine mutants of Salmonella typhimurium. Hydromethylnon. germanica.5-0.2 4.0) 1. not surprisingly.9 with the natural acetogenins and from 0.9-7.2-2. (Asta Laboratories.9 (0.6 (0.1 5.3) 0. this is a definite safety factor should someone ingest excessive amounts of these materials either intentionally or unintentionally. of paw paw bark.3 3. Resistance Ratios for Annonaceous Acetogenins and Conventional Synthetic Toxicant Baits for Second and Fifth Instars of Blattella Germanica compound type natural active ingredienta parviflorin asimicin sylvaticin bullatalicin annomontacin gigantetrocin A cypermethrin chlorpyrifos hydramethylnon propoxur bendiocarb second instar RRa (95% CL) 0.3 2.0)* 3.9 (0.2 4. containing mix- Figure 11. These compounds are proven to induce emesis in pigs.7 (1.1 128.2) 0.0-2. into integrated pest management programs to control resistant B.3 synthetic a Number of days before death of 50% of the population following exposure to toxic baits at a dose of 1000 ppm. There was a single response value for cypermethrin against fifth instars of the Jwax strain. LT50 Valuesa for German Cockroach Second Instars compound type natural active ingredient parviflorin asimicin sylvaticin bullatalicin annomontacin gigantetrocin A cypermethrin chlorpyrifos hydramethylnon propoxur bendiocarb Jwax (susceptible strain) 1.0 2.3-2. no significant differences exist between the probit levels of mortalities being compared.1-0.8 181. 1999.6-4.4 b 0. Table 2. and one slight positive (2.2 0.4-10.1) 0.1 34. the fifth instars ranged from 0.2 10.4) 0.7 20.8 with the synthetic compounds.3 2. The activities of 44 Annonaceous acetogenins were evaluated in the yellow fever mosquito larva microtiter .5 10.1-15.7 (-) 0.5-2.22 The high mortality observed with the low resistance ratios.1 Invited Review synthetic a Number of days before death of 50% of the population following exposure to toxic baits at a dose of 1000 ppm.1-14.512 Journal of Natural Products.5% above control) occurred after enzyme activation of the extract.9 (0. an electron-transport complex III inhibitor. Table 3.0)* 0.6-1.7) 2. In some instances.9 (1.6 5.5) 2. Vol.5 (1.4 10.2 with the natural acetogenins and from 1.1 39.8-1.8-1. No growth-regulation effects were caused by any of the compounds tested.

by R01 Grant No. Acknowledgment.5. A-549 ED50 1. biologists. 1766. 2919. pharmacognosists. 241. 1468.7. and X. 1732.0° (c 0. HT-29 ED50 2. 333. film. Recent investigations indicate that the cytotoxic effects of Annonaceous acetogenins can thwart classical MDR in the adriamycin-resistant human mammary adenocarcinoma (MCF-7/Adr) cell model. 62. A-498 ED50 1. Biological activities (µg/mL): BST LC50 < 3.Invited Review Journal of Natural Products. MCF-7 ED50 3. CHCl3). cm-1): 3418. synthetic targets can also include a wide diversity of analogues based on the SAR generalizations. 1319. cm-1): 3415.0 × 10-1. The pesticidal properties of the Annonaceous acetogenins make them well-suited for the control of insect pests including cockroaches in an urban setting. HT-29 ED50 1. MW 624) White amorphous powder. 141. and phytochemists. No.A acknowledges generous financial support from Mrs. 223. in part. botanists.8. per-MTPA esters (1H NMR). 2850.5 × 10-2.7.4-cis)-gonioneninone 3. respectively. as mentioned above. 2359. 1717. CA 30909 from the National Cancer Institute. film. To meet the demands of further in vitro and in vivo pharmacological evaluation. 141. IR (νmax. we especially encourage the synthesis of those selectively cytotoxic acetogenins that are rare in nature. . 325.g. A concentration of only 1000 ppm in a dietary formulation produced high mortality and was associated with delays in nymphal development of second and fifth instars of both susceptible and resistant German cockroaches. Vol. The studies described in this review carried out at Purdue University were supported. selectivity. IR (νmax. 205. MS: EIMS m/z 351. as determined using the natural compounds. NMR: 1H NMR (500 MHz. 1206. 241. 2922. nm): 208 (log 3. The high potency. squamotacin. 1466. Compounds showing LC50 values below 1. The SAR observed indicated that the compounds bearing adjacent bis-THF rings with three hydroxyls groups are the most potent. Further research is now necessary to develop refined pesticidal strategies for the inclusion of such highly effective and environmentally friendly formulations to control pests.. 13C NMR (125 MHz. CDCl3). PC-3 ED50 2. 223.2.9 × 10-1. 235. which is specific for prostate tumor cells. MeOH. PACA-2 ED50 4. CDCl3). 333. 323. 13C NMR (125 MHz. MW 622) 2. 253. Source: Goniothalamus giganteus. 1999.6 × 10-2. Biological activities (µg/mL): BST LC50 2. MCF-7 ED50 1. 263.4-trans)-gonioneninone White amorphous powder. PC-3 ED50 1. 307. stem bark. 205. Source: Goniothalamus giganteus. Conclusions The biological properties of the Annonaceous acetogenins continue to attract the attentions of biochemists.L. UV (λmax. F. gonioneninone (reported as a cis and trans mixture)108 (C37H66O7. chemists. 255.5. Marilyn Cochran of San Angelo.67 mg/L or ppm (parts per million). [R]D: +16. wide chemical and biological diversity. stem bark. Thorough in vivo studies are now needed to support the results proposed from the above-mentioned in vitro work. entomologists. 3 513 plate (YFM) assay. Annonaceous Acetogenins Reported between June 1995 and August 1998 (* Indicates Relative Stereochemistry) Mono-THF Acetogenins 1. CHCl3).1 × 10-1. e. CDCl3).5. (2. per-MTPA esters (1H NMR). and effectiveness of these compounds against resistance could well make them become the next class of useful natural antitumor and pesticidal agents.1° (c 0.0 ppm in this assay are usually considered significant as new lead candidates for pesticidal development. goniotetracin39 (C37H68O7. MS: EIMS m/z 351.1 and 0. A-549 ED50 3. TX. Derivatives: peracetate (1H NMR). Bullatacin and trilobin gave the best activities against YFM with LC50 values of 0.Q.-X.0 × 10-1. 2851. (2. PACA-2 ED50 2. [R]D: +16.52). Derivatives: peracetate (1H NMR). Appendix 1 Table 4. 281. CDCl3).05. 281.97 The results clearly demonstated that most acetogenins have potent pesticidal properties. A-498 ED50 2. National Institutes of Health. 263.056. NMR: 1H NMR (500 MHz. acknowledges fellowship support from the Purdue Research Foundation.9.

[R]D: +6. 3 Table 4.1. MS: EIMS m/z 379. (2. nm): 218 (log 3.7. No. 311. 361.8. cm-1): 3445. 2926. film.4.015.2. (2. CDCl3). 293. Biological activities (µg/mL): BST LC50 2.2. 193. HT-29 ED50 1.5. 2916. xylomaticinone39 (reported as a cis and trans mixture) (C37H69O7.4-cis)-squamoxinone 7. squamoxinone109 (reported as a cis and trans mixture) (C37H68O7.4-cis)-xylomaticinone 9. cis-4-deoxyannoreticuin*109 (C35H64O6.2. CDCl3). 311.2 × 10-1. 255. NMR: 1H NMR (500 MHz. 227. 279. MW 580) Invited Review White amorphous powder. HT-29 ED50 1.61). Derivatives: per-MTPA esters (1H NMR). A-498 ED50 1. Biological activities (µg/mL): BST LC50 8. 273. IR (νmax. 319.4.4 × 10-2. CHCl3). CH2Cl2). Vol. CDCl3). 2848. 13C NMR (125 MHz. Source: Annona squamosa. stem bark.5 × 10-3. MCF-7 ED50 2. 13C NMR (125 MHz. 291. HT-29 ED50 1. 1470. cm-1): 3423. stem bark.0. stem bark. 1755. 371. UV (λmax. A-498 ED50 2. PC-3 ED50 2.8. 4-deoxyannoreticuin*109 (C35H64O6. MCF-7 ED50 1. 297. 337. nm): 203 (log 3. MS: EIMS m/z 407. 1999. MCF-7 ED50 7. NMR: 1H NMR (500 MHz.1. PACA-2 ED50 7. [R]D: +6. 293. PC-3 ED50 2. MS: EIMS m/z 345. 1070. Source: Annona squamosa. (2.7.4-trans)-xylomaticinone White wax. 389.7. 275.023. CDCl3). UV (λmax. . MW 624) 6.514 Journal of Natural Products. 343. 1716.015.4-trans)-squamoxinone White amorphous powder. 1755. 193. 1756. MeOH. PACA-2 ED50 1. 2850. Biological activities (µg/mL): BST LC50 6.4 × 10-4. 13C NMR (125 MHz.7. UV (λmax. [R]D: +26.9. A-549 ED50 2.08.20). 2854. 13C NMR (125 MHz. 2854. MS: EIMS m/z 345. CHCl3).4 × 10-1. 241. A-549 ED50 1. PACA-2 ED50 2.8° (c 0. 309. CDCl3). stem bark. Biological activities (µg/mL): BST LC50 0.3° (c 0. CDCl3). 5. (Continued) Mono-THF Acetogenins (Continued) 4. A-549 ED50 1. 1916. Source: Annona squamosa. film. A-498 ED50 1. cm-1): 3423. NMR: 1H NMR (500 MHz. 275. MCF-7 ED50 1. IR (νmax. 211. MW 624) 8.7 × 10-2. [R]D: +13. PACA-2 ED50 4. MeOH.6 × 10-4. film. 2919.9. cm-1): 3454.8° (c 0. (2. Derivatives: per-MTPA esters (1H NMR).9.4 × 10-2. NMR: 1H NMR (500 MHz. A-498 ED50 1. MeOH.7. CDCl3). IR (νmax. Derivatives: per-MTPA esters (1H NMR). 141. nm): 218 (log 3. HT-29 ED50 7. 211. film.61). CDCl3). A-549 ED50 3. PC-3 ED50 5.2° (c 0.9. CH2Cl2). Derivatives: per-MTPA esters (1H NMR). 1755. MW 580) White amorphous powder. Source: Annona squamosa. 62. PC-3 ED50 2. IR (νmax.

5 × 10-1. 1191. 203.4 × 10-1. 301.4-cis)-squamoxinone C 14. CDCl3).6 × 10-2. 2360. 245. MCF-7 ED50 5. PC-3 ED50 1. 13C NMR (125 MHz. 1721. PC-3 ED50 2.4 × 10-3.35). [R]D: -13. PC-3 ED50 5. A-498 ED50 6.8 × 10-7. CDCl3). 395.023. 2850. Derivatives: per-MTPA esters (1H NMR).4 × 10-3. 1318. . 389. MeOH. 4-deoxyannomontacin47 (C37H68O6. Derivatives: per-MTPA esters (1H NMR). CDCl3). CDCl3). IR (νmax. 1740.4 × 10-1. nm): 203 (log 2. 13C NMR (125 MHz. 2851. NMR: 1H NMR (500 MHz. 263. CH2Cl2). CDCl3). MW 608) White wax. 3 515 Mono-THF Acetogenins (Continued) 10. (2. UV (λmax. UV (λmax. PC-3 ED50 3.0 × 10-2.3 × 10-6. Biological activities (µg/mL): BST LC50 4. PACA-2 ED50 5. 13C NMR (125 MHz. A-549 ED50 2. IR (νmax. 319. 1770. cm-1): 3368. film.6° (c 0. 1470. 303. Source: Goniothalamus giganteus.8 × 10-3.1 × 10-1. 255. 841.4-trans)-squamoxine B White amorphous powder. 359. [R]D: +23. MS: EIMS m/z 389. cm-1): 3443. 62. 225. 1470.7 × 10-3. 1999. Derivatives: per-MTPA esters (1H NMR). 377. Biological activities (µg/mL): A-549 ED50 7. stem bark. stem bark. IR (νmax.24.Invited Review Table 4. 269. NMR: 1H NMR (500 MHz. 1374.7 × 10-3. CDCl3).46). 2921. cm-1): 3444. 373. nm): 218 (log 3. MCF-7 ED50 1. 1467. MCF-7 ED50 5. A-498 ED50 1. Source: Annona squamosa.7 × 10-1. HT-29 ED50 3. CDCl3). HT-29 ED50 1.0 × 10-5.0 × 10-3. A-549 ED50 6. stem bark. 239. 1328.7 × 10-3. 1058. Derivatives: per-MTPA esters (1H NMR).86).20. PACA-2 ED50 1. 1715. A-549 ED50 3. (2. MCF-7 ED50 1. 337.3° (c 0. MeOH. squamoxinone C*42 (reported as a cis and trans mixture) (C35H64O7.4-cis)-squamoxine B 12. CH2Cl2). Biological activities (µg/mL): BST LC50 1. nm): 207 (log 3. 1086. HT-29 ED50 2. nm): 228 (log 2. (2. 255. 1455. MeOH. A-498 ED50 4.5 × 10-7. HT-29 ED50 3. 301. 2921. (Continued) Journal of Natural Products. squamoxine B*42 (reported as a cis and trans mixture) (C37H68O7. 253.3 × 10-4. stem bark.9° (c 0. Source: Goniothalamus giganteus. UV (λmax. 1770.6 × 10-1. [R]D: +10. MW 578) Whitish wax. 337. Source: Annona squamosa. 391. MW 624) 13. MW 630) 11. goniotrionin10 (C35H62O6. 13C NMR (125 MHz. film. 339. Vol.7 × 10-2. film. 15. IR (νmax. 2916.4-trans)-squamoxinone C White wax.5 × 10-1. CHCl3). 1068. 1705. (2. cm-1): 3390. PACA-2 ED50 8. 2916. CDCl3).3 × 10-1. MS: EIMS m/z 413. Biological activities (µg/mL): BST LC50 9. 1742. MeOH. NMR: 1H NMR (500 MHz.0 × 10-3. MS: EIMS m/z 297. 321. A-498 ED50 2. film. UV (λmax.1 × 10-3. PACA-2 ED50 9. TMS (EIMS). 251. 221.5 × 10-3. 281. NMR: 1H NMR (500 MHz.85).060. MS: EIMS m/z 425. No. 2849. 319. peracetate (1H NMR). 1028.

2920. 305. A-498 ED50 7. CDCl ).4. leaves. 241. cm-1): 3461. 339.6 × 10-1.4 × 10-3. stem bark. 357. 269. NMR: 1H NMR (500 MHz. leaves. 199. 251. 355. 1754. A-498 ED50 2. 299.1. HT-29 ED50 2. A-498 ED50 1. 123. 281. 393. IR (νmax. 1182. 13C NMR (125 MHz. A-549 ED50 2. 393. 1743. (2. Source: Annona glabra. 263. UV (λmax. 221. 211. 305. A-549 ED50 1. 319.65). IR (νmax. 407. 375.3. CDCl3). 357. NMR: 1H NMR (500 MHz. 2850.4-cis)-annomontacinone 17. HT-29 ED50 5. 341. Biological activities (µg/mL): BST LC50 10. UV (λmax. film. 411. A-549 ED50 1. MW 624) Invited Review 16. 13C NMR (125 MHz. MW 596) Whitish waxy solid. PC-3 ED50 9. MW 628) White solid. 269. 1318. 141.022. No.9 × 10-1. TMS (EIMS). 20. film. nm): 220 (log 3. IR (νmax. glacin A25 (C35H64O7. 2849. 163. CDCl3). 245. IR (νmax.6° (c 0. NMR: 1H NMR (500 MHz. 1550. 287.83). 213. MCF-7 ED50 4.6° (c 0. MeOH.4-trans)-annomontacinone Whitish wax. CDCl3). 1460. leaves. 375. muricoreacin*110 (C35H64O9. murihexocin*110 (C37H68O7. formal acetal (1H NMR). HT-29 ED50 2. Biological activities 3 3 µg/mL): BST LC50 1. nm): 220 (log 3.3.3.8.0. 323.5 × 10-2. 1075. nm): 218 (log 3. CHCl3).5. [R]D: +1. 18. film. 411. 251. 1075. NMR: 1H NMR (500 MHz. 337. 123. CHCl3). PACA-2 ED50 6. MCF-7 ED50 3. 1464. [R]D: +37.69). MS: EIMS m/z 429.04. PC-3 ED50 2.2.06. PC-3 ED50 8. 2915. Biological activities (µg/mL): BST LC50 19. 141.1 × 10-1. [R]D: +13. per-MTPA esters (1H NMR). MS: EIMS m/z 429. Biological activities (µg/mL): BST LC50 3.6 × 10-3. 181. 199. 301. MW 628) White solid.8 × 10-3. CDCl3). Derivatives: per-MTPA esters (1H NMR). 1203. 269. Source: Annona muricata. 1734. A-498 ED50 1. Source: Annona muricata. 203. 171.7 × 10-1. 1717. MS: EIMS m/z 425. HT-29 ED50 1. CDCl3). 2849. MeOH. CDCl3). 141. 239. cm-1): 3367. 3 Table 4. 2851. MeOH.8 × 10-1. 233. 1474. PACA-2 ED50 8. UV (λmax. PC-3 ED50 1. 181. .3. 2916. (Continued) Mono-THF Acetogenins (Continued) annomontacinone47 (reported as a cis and trans mixture) (C37H68O7.1 × 10-1.5. CHCl3). 223.6. 62. 13C NMR (125 MHz. MCF-7 ED50 3.5° (c 0.0° (CHCl3). PACA-2 ED50 2.3 × 10-1.6 × 10-1. 257. cm-1): 3347. Vol. 19.516 Journal of Natural Products. PACA-2 ED50 4. 323. Source: Goniothalamus giganteus. 1717. 287. 727. A-549 ED50 2. CDCl ). cm-1): 3433. 1470. film. 341. (2. 1999. 2919. 339. 13C NMR (125 MHz.1 × 10-1. MCF-7 ED50 1. 193. 177. Derivatives: peracetate (1H NMR). 251. [R]D: +6. 1743.3. 195.

MW 644) White waxy solid. 277. 13C NMR (50 MHz.8 (log 4. PC-3 ED50 -2. No. 2929. Derivatives: per-MTPA esters (1H NMR). MS: EIMS m/z 363. Source: Annona coriacea. 291. NMR: 1H NMR (400 MHz. 295.08. 1543. CDCl ). CHCl3). Source: Annona coriacea. IR (νmax. 343. HT-29 ED50 8. Derivatives: per-MTPA esters (1H NMR). 2921. MeOH. MW 644) White waxy solid. 1120. glabracin B25 (C35H64O7. MeOH. cm-1): 3423. gardnerinin35 (reported as a pair of epimers) (C35H64O9.2 × 10-2. coriaheptocin A*40 (C35H64O10. 247. [R]D: +25° (c 1. Source: Annona glabra. UV (λmax. 265. 1999. 1318. 1465.0° (c 1. nm): 207. UV (λmax. MW 546) White waxy solid. 1066. 223. 2929. 141. film. MeOH. Derivatives: peracetate (1H NMR). CHCl3). 5. nm): 208. Source: Annona coriacea.6).6. film.0° (c 0. NMR: 1H NMR (400 MHz.8° (CHCl3). UV (λmax. 3 517 Mono-THF Acetogenins (Continued) Whitish waxy solid. 327. UV (λmax. Derivatives: peracetate (1H NMR).5. [R]D: +8. CDCl3). 13C NMR (50 MHz. 269. 62. 1275. Source: Annona coriacea. MeOH. MW 572) White oil. Vol. [R]D: +6. MeOH.00.7 × 10-1. [R]D: +4. A-498 ED50 2. 265. roots. CDCl3). acetonide (1H NMR). MS: EIMS m/z 397.65). A-549 ED50 1. 273. roots. CDCl3). 2856. 277. 309. 1452. CHCl3). UV (λmax. 233. PACA-2 ED -2. 247. CDCl3). 379. film. (Continued) 21. CDCl3).Invited Review Table 4. NMR: 1H NMR (500 MHz. cm-1): 3488. 223. IR (νmax.6 × 10 50 1. 3 23. leaves. CDCl ). nm): 221 (log 3.5 × 10 22.7 × 10-2. acetonide (1H NMR). roots. MW 628) . MW 596) Journal of Natural Products. 251. NMR: 1H NMR (400 MHz. 25. [R]D: +19° (c 1. Derivatives: per-MTPA esters (1H NMR). CHCl3). nm): 208 (log 3. cm-1): 3522. 1075.0). CDCl3). nm): 207 (log 3. 1761.2. IR (νmax. coriaheptocin B*40 (C35H64O10.2 (log 4. 13C NMR (50 MHz.40). 24. coriacyclodienin111 (C37H64O7. roots. CDCl ). 2850. MCF-7 ED50 5. 13C NMR (125 MHz. Biological activities 3 3 (µg/mL): BST LC50 2. 199. 13C NMR (50 MHz. 2856. CDCl3).87). MS: EIMS m/z 295. coriacycloenin111 (C35H62O4. 1736. 1762. NMR: 1H NMR (400 MHz. 1076.3.

MeOH). roots. donnaienin A32 (reported as a pair of epimers) (C35H64O7. donnaienin C34 (reported as an epimeric pair) (C37H66O9. NMR: 1H NMR (500 MHz. 543. CHCl3). UV (λmax. roots. acetonide (1H NMR). 211. 2923. 349. NMR: 1H NMR (500 MHz. donnaienin B32 (reported as an epimeric pair) (C35H64O8. TMS (EIMS). 561.6. MW 596) 28. 928. 3 TMS (EIMS). 329. 311.518 Journal of Natural Products. donnaienin A 29. per-MTPA esters 3 3 (1H NMR). 483. 343. 251. 465. MS: EIMS m/z 367. 309. NMR: 1H NMR (500 MHz. UV (λmax. 313. Source: Goniothalamus donnaiensis. Mp: 78-80 °C. Vol. film. Mp: 70-72 °C.07. 2922. 13C NMR (125 MHz. CH3OH). 1752. MS: EIMS m/z 413. Bel 7402 IC50 >10.0° (c 0. 1999. MeOH.07.6° (c 0. 291. MeOH. per-MTPA esters (1H NMR). donnaienin B 31. roots. cm-1): 3395. 1072. 1467. Derivatives: phenylhydrazone (1H NMR). CDCl ). MS: EIMS m/z 597. 34-epi-gardnerinin White waxy solid. [R]D: -7. 297. per-MTPA esters (1H NMR). 379. 13C NMR (125 MHz. TMS (EIMS). 331. IR (νmax. 1762. 269. gardnerinin Invited Review 27. 279. Biological activities (µg/mL): KB IC50 >10. nm): 208 ( 6815). Biological activities (µg/mL): KB IC50 <1.09. acetonide 3 (1H NMR). cm-1): 3390. 3 Table 4. 1465. 13C NMR (125 MHz. HCT-8 IC50 6. (Continued) Mono-THF Acetogenins (Continued) 26. CDCl3). nm): 205 ( 6831). 579. CDCl ). 395. IR (νmax. 361. 1749. donnaienin C . 2852. 2850. Biological activities (µg/mL): KB IC50 10. 377. MW 654) 32. 229. 2920. 293. CDCl ). film. 2852.0° (c 0. Mp: 96-98 °C. film. 261. HCT-8 IC50 <10. No. 34-epi-donnaienin A White amorphous powder. 447. MW 612) 30. Derivatives: phenylhydrozone (1H NMR). 34-epi-donnaienin B White amorphous powder. Source: Goniothalamus gardneri. CDCl3). 62. [R]D: -19. [R]D: +14. cm-1): 3386. acetonide (1H NMR). IR (νmax. CDCl ). 1466. Derivatives: phenylhydrazone (1H NMR). 525. Source: Goniothalamus donnaiensis.

4. UV (λmax. 1466. nm): 218 (log 3. Biological activities (µg/mL): BST LC50 18. 1736. Derivatives: acetonide (1H NMR). IR (νmax. A-498 ED50 1. MeOH. HCT-8 IC50 >10. . 1469. [R]D: +12. 205. MS: EIMS m/z 377. film. UV (λmax. 1376. 37. 62. 199. Source: Goniothalamus donnaiensis. NMR: 1H NMR (400 MHz.4. MeOH). 271. Derivatives: phenylhydrazone (1H NMR). 141.25. 325. 367.7 × 10-1.05. 286. 2920. IR (νmax. A-498 ED50 1. CDCl3). per-MTPA esters (1H NMR). CDCl3). MCF-7 ED50 1. 385. 343. 353. 1439. MW 612) White amorphous powder. seeds.5 × 10-1. muricapentocin*113 (C35H64O8. TMS (EIMS). Derivatives: acetonide (1H NMR). roots. 341.1 × 10-1. film. Derivatives: peracetate (1H NMR). 213. NMR: 1H NMR (500 MHz. 141. 317. annomuricin E*113 (C35H64O8. 2850.9). (Continued) Journal of Natural Products. MW 596) Solid. PACA-2 ED50 5. 227. MW 612) White solid.9 × 10-1. HT-29 ED50 6. 361. 1032. 199. MS: EIMS m/z 379. 231. 1743. 307.0° (c 0. 13C NMR (50 MHz. MS: EIMS m/z 377. Biological activities (µg/mL): BST LC50 1. 437. [R]D: +0° (c 0. MW 612) White solid.5 × 10-1. 349. Bel IC50 7. MeOH). 241.7. 2851. cm-1): 3367. IR (νmax.Invited Review Table 4. 269. [R]D: +30° (c 0.76). 123. Source: Annona glauca. 195. cm-1): 3429. MeOH. nm): 209 (log 3. 2920. 123. 13C NMR (125 MHz. 756. A-549 ED50 1. 241.2. 269. film. Biological activities (µg/mL): KB IC50 >10. Vol. 269. leaves. 271. 13C NMR (125 MHz. PC-3 ED50 1. NMR: 1H NMR (500 MHz. Biological activities (µg/mL): KB IC50 >10.1. 349.1 × 10-2. 2850. Source: Annona muricata. MeOH). IR (νmax.0 × 10-2. IR (νmax. 335. cm-1): 3381. 331. MeOH). 141. 1061. 36. MS: EIMS m/z 455. CDCl3). 34. CHCl3). A-549 ED50 1.04. leaves. 269. 199. 2920. EtOH. 251. 177. 281. No. PACA-2 ED50 2. Mp: 90-92 °C. 2851. 309. 401. 299.4° (c 0. 34-epi-donnaienin C White amorphous powder. UV (λmax. 952. 359. 2851. film.4 × 10-1. 359. 419. 1746. 299. 2920. CDCl3). 367. cm-1): 3402. 307. 289. 2920. 263.9. Bel IC50 6. PC-3 ED50 4. MCF-7 ED50 1. MS: EIMS m/z 385. 341. 245.7. CDCl3). 331. Mp: 92-94 °C. 3 519 Mono-THF Acetogenins (Continued) 33. 251. 289.8. [R]D: +8. CDCl3). 13C NMR (125 MHz. 343. NMR: 1H NMR (500 MHz.54). 291. HCT-8 IC50 >10. Source: Goniothalamus donnaiensis. 281. glaucafilin112 (C35H65O7. 1743. CDCl ). [R]D: +17. 1744. cm-1): 3398. 313.5 × 10-1. 251. CDCl3). donnaienin33 (C35H64O8. formal acetal (1H NMR).08. CDCl3). film. 1999. HT-29 ED50 7. Source: Annona muricata. 3 35. 13C NMR (125 MHz. CDCl3). NMR: 1H NMR (500 MHz. roots. nm): 220 (log 3. 325. 223.5° (c 0. 253. 1458.

343. 225. TMS (EIMS). 1050. 359. CDCl ). MS: EIMS m/z 595.10. cm-1): 3413. MW 622) Invited Review Amorphous powder. 3 Table 4. NMR: 1H NMR (500 MHz. CDCl3). 413. 289. IR (νmax. Source: Goniothalamus donnaiensis. 121. CDCl3). 523. 13C NMR (100 MHz. 379. cis-goniodonin31 (reported as an epimeric pair) (C35H64O8. 377.271. 251. (2. 523. CDCl3). IR (νmax. 559. . 2921. 307. 2. 291. 309. 475. 1735. 257. 395. film. Vol. 1460.520 Journal of Natural Products. Source: Annona glabra.4-cis)-isomurisolenin 44. 377. 343. 1999. per-MTPA esters (1H NMR). 157. 211. goniodonin 40. goniodonin31 (reported as an epimeric pair) (C35H64O8. 157. CDCl3).5 × 10-2. 13C NMR (125 MHz. CDCl3). 249. NMR: 1H NMR (500 MHz. cm-1): 3500. 800. 373.4° (c 0. 271. 379. Source: Goniothalamus donnaiensis. 361. NMR: 1H NMR (400 MHz. 361. 265. MW 612) 39. 1250. [R]D: +3. 395. MeOH). 341.7 × 10-2. 325. 257. 577. 341. MS: EIMS m/z 391. 2. 267. 289. 139. NMR: 1H NMR (400 MHz. CDCl ).4 × 10-1. Biological activities (µg/mL): HCT-8 IC50 <10. 15 ED50 1. seeds. MW 612) 41. (2. 2860. 1465. 1734. 114 (reported as cis and trans mixture) (C H O . MeOH). glabranin23 (C37H66O7. 139. 559. 239. MS: EIMS m/z 493. CDCl3). [R]D: +32.31. 13C NMR (125 MHz. CCM2 ED50 8.8° (c 0. Biological activities (µg/mL): Hep. roots. 541. roots. 221.17. cm-1): 3514. 291. 1760. 307. per-MTPA esters (1H NMR). 3 3 TMS (EIMS). 541. 577. Source: Annona reticulata. 413. Hep G2 ED50 4. 2910. No. Derivatives: peracetate (1H NMR). 2920. 34-epi-goniodonin White amorphous powder. 1467. Mp: 78-80 °C. 269. KB ED50 1.9° (c 0. Derivatives: phenylhydrazone (1H NMR). 121. seeds. 2852. 2851. 13C NMR (100 MHz. 295. 239. 34-epi-cis-goniodonin White amorphous powder. cis-goniodonin 42. Mp: 80-82 °C. MW 578) isomurisolenin 35 62 6 43. CHCl3). film. 325. 141. 293. 62. [R]D: +3. IR (νmax. Biological activities (µg/mL): HCT-8 IC50 <10. (Continued) Mono-THF Acetogenins (Continued) 38. Derivatives: phenylhydrazone (1H NMR). 359. MS: EIMS m/z 595. 1710. 221.4-trans)-isomurisolenin White waxy solid. film.

1530. 141. NMR: 1H NMR (500 MHz. 1075. CDCl3).2 × 10-4.2 × 10-6. cm-1): 3453. Source: Annona glabra. 13C NMR (125 MHz. UV (λmax. [R]D: +4. 1630.96). PACA-2 ED50 2.8° (c 0. 269. MS: EIMS m/z 425. 1467. 1551.005. MeOH. 377. stem bark. 207. NMR: 1H NMR (500 MHz. Biological activities (µg/mL): BST LC50 1.Invited Review Table 4. 1318. nm): 218 (log 3. Biological activities (µg/mL): BST LC50 4. Biological activities (µg/mL): BST LC50 2.3 × 10-3. Source: Annona squamosa. HT-29 ED50 5. HT-29 ED50 5. IR (νmax. MCF-7 ED50 >1. MCF-7 ED50 6. leaves. 289. IR (νmax.48). Derivatives: per-MTPA esters (1H NMR).4 × 10-4. 62. 337. PC-3 ED50 >1. 13C NMR (125 MHz.016. Source: Annona glabra.7° (CHCl3). 301. PC-3 ED50 2. UV (λmax. MW 624) White waxy solid. 325. UV (λmax. 49. 307. 3 521 Mono-THF Acetogenins (Continued) 45. Biological activities (µg/mL): BST LC50 4. annoglacin A26 (C37H69O7. 13C NMR (125 MHz. CDCl3). mosinone105 (reported as a cis and trans mixture) (C37H64O7.57). MW 624) White waxy solid. CDCl3). Source: Annona squamosa. (Continued) Journal of Natural Products. A-498 ED50 >1. 1999.0 × 10-3. 225. MW 594) White waxy solid. 1512. MeOH. MCF-7 ED50 >1. 1528.8 × 10-3. MS: EIMS m/z 425. (2. No. 337. 225. [R]D: +11. A-549 ED50 9. NMR: 1H NMR (500 MHz. .0° (CHCl3).4 × 10-1.6 × 10-4. Derivatives: per-MTPA esters (1H NMR). HT-29 ED50 >1.7 × 10-1. 233. 673. 301. annoglacin B26 (C37H69O7. A-498 ED50 >1 × 10-1. 13C NMR (125 MHz.3 × 10-3. 791. 207. 2280. 1075. NMR: 1H NMR (500 MHz. Derivatives: per-MTPA esters (1H NMR). MS: EIMS m/z 395. 251. CH2Cl2). PACA-2 ED50 1. 1409. PC-3 ED50 8.0 × 10-1.4-trans)-mosinone White waxy solid.1 × 10-7. MW 620) 47. 307. mosin B*105 (C35H62O7. 46. nm): 202 (log 2.2 × 10-4. (2. nm): 219 (log 3. 2920. MeOH. A-498 ED50 4. nm): 222 (log 3.3 × 10-3.9 × 10-1. 269.5° (c 0. 1275. 1742. CDCl3). A-549 ED50 >1. CDCl3). MCF-7 ED50 9. Derivatives: per-MTPA esters (1H NMR). 407. 855. 2851.9 × 10-1.4-cis)-mosinone 48. Vol. 251. 359. MeOH. CDCl3). 1106. 407. 2850.2 × 10-2. PACA-2 ED50 5.4 × 10-1. CDCl3). A-498 ED50 9. PC-3 ED50 3. HT-29 ED50 >1. 355. PACA-2 ED50 1. MS: EIMS m/z 325. A-549 ED50 2.0 × 10-1. [R]D: +15. 965. 1657. 289. 850. CDCl3). 141. film. 319. 1548. CH2Cl2). UV (λmax. film. A-549 ED50 5. cm-1): 3413. 355.62). 319. stem bark. 2920. 1462. 1022. 1735. 233.2 × 10-1. 1321. leaves. [R]D: +15.

CDCl3). CDCl3). roots. IR (νmax. Biological activities (µg/mL): BST LC50 1. 249. Source: Annona muricata. nm): 216 (log 3.007. UV (λmax. 297. 267. 1321. MeOH). 1080. 297. UV (λmax. PACA-2 ED50 1. 111. 227. 1324.40. Mp: 60-62 °C. 111.58). MeOH. . 1124. nm): 219. 1033. 13C NMR (50 MHz. MeOH. 1760. 3 3 52. MW 564) White powder. Source: Annona muricata. 97. [R]D: +22° (c 0. 1077. 97. 249. IR (νmax. NMR: 1H NMR (400 MHz. [R]D: +18° (c 0. 227. Mp: 62-64 °C. 1760.61). MW 592) White powder. 968. cis-solamin*115 (C35H65O5. 13C NMR (50 MHz. 2840. MCF-7 ED50 >1. 255.0 × 10-1. 295. MS: EIMS (m/z) 337. CDCl3). MeOH). 53.63). IR (νmax. CDCl3).15. 753. 1073. nm): 220. MW 592) White powder. CDCl3). MW 564) White powder. 251. 845. NMR: 1H NMR (400 MHz. 13C NMR (50 MHz. cis-uvarimicin I*115 (C37H69O5. Derivatives: per-MTPA esters (1H NMR).2 (log 3. No.6 (log 3. UV (λmax. 1120. 1471. 13C NMR (125 MHz.5 × 10-1. NMR: 1H NMR (500 MHz. 1114. CDCl3). 1034. 1032. 225. 97. 1759.2 × 10-4. 1033. 2916. film. 717. 207. 1325. MS: EIMS m/z 347. cis-panatellin*115 (C35H65O5. UV (λmax. 111. 51. 717. film. film. 3 Table 4. IR (νmax. Source: Annona squamosa. 319. 962. [R]D: +20° (c 0. 111. 963. 289. cm-1): 3420. A-549 ED50 6. cm-1): 3420. cm-1): 3422.55.3 (log 3. 295. cm-1): 3423. 97. CDCl3).522 Journal of Natural Products. mosin C105 (C35H62O7. 267. CH2Cl2). 54. 2841. 1474. 279. MS: EIMS m/z 347. PC-3 ED50 >1. MeOH. 1999. MW 594) Invited Review White waxy solid. A-498 ED50 >1. 1762. 325. roots.65). 2916.60. NMR: 1H NMR (400 MHz. bark stem. 2916. MeOH. [R]D: -2. roots. film. (Continued) Mono-THF Acetogenins (Continued) 50. 1078. cis-uvarimicin IV*115 (C37H69O5. 2840. CDCl3). MeOH. 13C NMR (50 MHz. MS: EIMS m/z 319. 2917. MeOH). nm): 217. 1120. UV (λmax. 742.56). [R]D: +20° (c 0. HT-29 ED50 >1. Source: Annona muricata. 1325.8 (log 3. NMR: 1H NMR (400 MHz. roots. CDCl ). Mp: 63-66 °C. Source: Annona muricata. 199. Mp: 60-62 °C. 1473. nm): 221. 62.7° (c 0. CDCl ). 965. MeOH). 2839. 307. 748. Vol. 751. 1471. MS: EIMS m/z 325.

CDCl3). 123. Derivatives: peracetate (1H NMR). 323. MS: EIMS m/z 423. nm): 220. 2849. HL-60 IC50 6. 2919. NMR: 1H NMR (500 MHz. 742. 389. 269.4. 153. NMR: 1H NMR (400 MHz. 1410. 453. NMR: 1H NMR (400 MHz. 1753. 62. 405. Mp: 60-62 °C. 2849. 419. 1474. tonkinin A*66 (C37H66O7. NMR: 1H NMR (500 MHz. 1999. roots. Source: Annona muricata. [R]D: +23° (c 0. Vol. 387. 968. 213. 181. 223. cm-1): 3423. CHCl3). IR (νmax. TMS (EIMS). HL-60 IC50 1. 269. MS: EIMS m/z 569. UV (λmax. 291.6° (c 1. 1068. CDCl3). 2839. MW 666) Waxy solid. 57. CDCl3). 1700. CDCl3). 13C NMR (125 MHz. 251. 1760. 1714. MW 592) White powder.18. 1738. 3 523 Mono-THF Acetogenins (Continued) 55. CDCl3). IR (νmax.20° (c 0. film. CDCl3). 13C NMR (50 MHz. 181. 543. 371. Biological activities (µg/mL): HCT-8 IC50 5. roots. TMS (EIMS). CHCl3).40. 1325. (Continued) Journal of Natural Products. 153. 59. 353. 111. 295. Source: Uvaria tonkinensis. [R]D: +28. Derivatives: peracetate (1H NMR). 56. MeOH. CDCl3). 309. 181. 405.59). 269. KB IC50 >10. Derivatives: peracetate (1H NMR). 1711. Mp: 98-100 °C. Biological activities (µg/mL): HCT-8 IC50 2. film. film. MS: EIMS (TMS) m/z 685. cm-1): 3357. 1120.0 × 10-2. 195.112. Mp: 95-96 °C.9 × 10-1. 337. 717. 915. 387.0. cis-reticulatacin*115 (C37H69O5. [R]D: +1° (c 0. Source: Disepalum anomalum. 1070. Source: Uvaria tonkinensis. 2911. 339. 2840. tonkinin B*66 (C37H66O7. 58. 2920. MeOH). Mp: 62-64 °C. Source: Annona muricata. [R]D: +19. . MW 622) Waxy solid. 111.Invited Review Table 4. MeOH. TMS (EIMS). No. 291.6 × 10-2. 958. 13C NMR (54 MHz. 13C NMR (50 MHz.8 (log )3.09° (c 0. 199. 199. roots. 309. 205. NMR: 1H NMR (270 MHz. CHCl3). film. 363. UV (λmax.6 (log 3. cis-reticulatacin-10-one*115 (C37H67O6. MW 606) White powder. 199. 335. 319. CDCl3). MeOH). dispalin38 (C39H71O8.63). A2780 IC50 >10. 1373. 353. 1073. MW 622) Crystal. cm-1): 3410. KB IC50 >10. 197. IR (νmax. IR (νmax. 2916. stem bark. 1068. 1032. A2780 IC50 >10. 335. 291. CDCl3). MS: EIMS m/z 393. 1751. 1464. CDCl3). 279. nm): 219. roots. 168.098. 1029. 509. cm-1): 3416. 1032. 613. 97. 209. 13C NMR (125 MHz. 97. MS: EIMS m/z 407. [R]D: +20.

IR (νmax. TMS (EIMS). Derivatives: acetonide (1H NMR). 2923. 425. roots. 341. Source: Uvaria tonkinesis. MeOH. 568. cm-1): 3465. nm): 215 ( 9600). 337. 469. Source: Annona muricata. 155. cm-1): 3430. 1759. 311. 64. Derivatives: TMS (EIMS). (Continued) Mono-THF Acetogenins (Continued) 60. cm-1): 3433. [R]D: +25. MW 624) Powder. tonkinin C*66 (C39H68O8. 465. A-498 ED50 6. Derivatives: peracetate (1H NMR). 371. CDCl3). 611. Mp: 97-99 °C. cm-1): 3379. CDCl ). 351.155. 311. [R]D: +24. 181.1 × 10 50 1. 293. 607.8° (c 0. 323. 293.651. 395. 13C NMR (125 MHz. [R]D: +12° (c 14. 431. Source: Uvaria tonkinensis. MW 666) Oil. Derivatives: TMS (EIMS). film. CHCl3). CDCl3). UV (λmax.8 × 10 50 1. 3 3 peracetate (1H NMR). 2919.7 × 10-1. 2852. per-MTPA esters 3 3 (1H NMR). 1082. NMR: 1H NMR (500 MHz. PC-3 ED -2 1. Biological activities (µg/mL): BST LC50 8. cm-1): 3395. 62. roots. 269. 301. 1741. IR (νmax. 181. HT-29 ED -1.524 Journal of Natural Products. Source: Uvaria tonkinesis. 503. MCF-7 ED50 1. CHCl3). 1030. 153. CDCl3). 269. 1468. film.6 × 10-1. PACA-2 ED50 3. Biological activities (µg/mL): HCT-8 IC50 8. 553.1. 289. 2920. 371. 269. 389.9.6 × 10 . 355. NMR: 1H NMR (500 MHz. TMS (EIMS). 2850. 311. 13C NMR (125 MHz. IR (νmax.92° (c 0. . 62. CDCl3). 155. 413. tonkinesin C*66 (C39H70O8. 168. 571. 13C NMR (125 MHz. film. tonkinesin B*66 (C37H68O7.026.049.2 × 10-4. 2855. Mp: 40-42 °C. CDCl3). NMR: 1H NMR (500 MHz. CDCl ). IR (νmax. 407. 1745. 1470. 295. CDCl ). 1077. KB IC50 >10. 13C NMR (125 MHz. MS: EIMS m/z 467. MW 664) Invited Review Amorphous powder. 61. 271. [R]D: +10. 337. Mp: 80-81 °C. HL-60 IC50 4. per-MTPA esters (1H NMR). 1747.6. 2918. 1999. 389. 405. MS: EIMS (TMS)m/z 701. Derivatives: TMS (EIMS). MS: EIMS m/z 625. MS: EIMS m/z 586. 355. IR (νmax. 1245. 407. CHCl3). 589. 479. 63. film. 319. 447. CDCl ). NMR: 1H NMR (500 MHz. [R]D: +26. annopentocin A116 (C35H64O8. 2850. 379. 2850.2° (c 0. CHCl3). MW 612) White amorphous powder. 1723.5° (c 0. roots. 335. 2930. 389. 1377. 461. MS: EIMS m/z 407. 293. 3 Table 4. 1737. MW 624) Powder. 319. 213. NMR: 1H NMR (500 MHz. 1255.119. CHCl3). film. A2780 IC50 >10. 387. 521. 337. A-549 ED50 1. CDCl3). Source: Uvaria tonkinesis. tonkinesin A*66 (C37H68O7. 13C NMR (125 MHz. No. roots. Vol. leaves. 385.

MW 612) 67. IR (νmax. nm): 214 ( 9750). HT-29 ED50 1. leaves. cm-1): 3470. TMS (EIMS).3 × 10-1. cm-1): 3425. NMR: 1H NMR (500 MHz. 271.0 × 10-1. per-MTPA esters (1H NMR). 271. nm): 205 ( 7750). 181. [R]D: +15° (c 10. 379. 407. 387. 289. 251. 586. CDCl3). TMS (EIMS). 223. 181. PACA-2 ED50 1.8 × 10-1. 199. . 295. 3 525 Mono-THF Acetogenins (Continued) 65. cm-1): 3400. Vol. 291. PC-3 ED50 2. 69. MCF-7 ED50 3. annopentocin B116 (C35H64O8. MeOH. MS: EIMS (TMS)m/z 701. Source: Annona muricata. A-498 ED50 2. 385. 405.7 × 10-2. leaves.4-trans)-annomuricin-D-one White powder.3. CDCl3).4-cis)-annomuricin-D-one 68. 295. 289. Source: Annona muricata. uvaribonone*134 (C39H68O8 MW 664) Waxy solid. 213. peracetate (1H NMR). 1740.2 × 10-1. 2845. 559. 521. leaves. [R]D: +15° (c 0.3 × 10-1.Invited Review Table 4. 2925. 1741. 1367. A-549 ED50 2. 13C NMR (125 MHz. PC-3 ED50 1.1 × 10-1. nm): 214 ( 9800). 1715. Derivatives: acetonide (1H NMR). 341. MW 612) White oil. MW 612) White oil. 568. annomuricin-D-one116 (reported as a cis and trans mixture) (C35H64O8. 213. TMS (EIMS). 153. CDCl3). 1720. No. Biological activities (µg/mL): BST LC50 1. 62. 2825. CHCl3). 1661.6. [R]D: +15° (c 10. 1999. 379. film. 271. 1465. 611. annopentocin C116 (C35H64O8. 539. 469. 413. 13C NMR (125 MHz. UV (λmax. 395. 611. MCF-7 ED50 3. 1455. 503. bark.6 × 10-1.1 × 101. 66. UV (λmax. 309. Source: Annona muricata. 317. formal acetal (1H NMR). film. PACA-2 ED50 4. 465. 1455. 521. Mp: 42-44 oC. 2835. Derivatives: acetonide (1H NMR). per-MTPA esters (1H NMR). 379.6. MS: EIMS (TMS)m/z 701. IR (νmax. A-498 ED50 3. 2930.6 × 10-1. 341. 317. 313. peracetate (1H NMR). 335. 2925. Biological activities: BST LC50 4. Source: Uvaria boniana. MeOH. CHCl3). film.1 × 10-2.4 × 101. 341. [R]D: +9° (c 11. PC-3 ED50 2. MS: EIMS (TMS) m/z 629. IR (νmax. NMR: 1H NMR (500 MHz. film. 2835. 469. 13C NMR (125 MHz. 449. 413. A-549 ED50 2. CDCl3). (2.497. 431. 503. 251. CDCl3). 359. PACA-2 ED50 <10-2.587. 1765. 1755. Biological activities (µg/mL): BST LC50 1. CDCl3). 323. Derivatives: per-MTPA esters (1H NMR). 269.1 × 10-1. (Continued) Journal of Natural Products. NMR: 1H NMR (500 MHz. CHCl3). 181. 289. 385. UV (λmax. NMR: 1H NMR (500 MHz. Derivatives: TMS (EIMS). cm-1): 3410. CHCl3). 181. MCF-7 ED50 6. HT-29 ED50 1. CDCl3).06. A-549 ED50 <10-2. HT-29 ED50 <10-2.8. A-498 ED50 1. MeOH. 1749. 431. IR (νmax. (2. CDCl3).2. 469. 323. 13C NMR (125 MHz. 2935. 125. MS: EIMS (TMS)m/z 604.

1755. MS: EIMS (TMS) m/z 554. 111. uvaribonianin*134 (C37H66O8 MW 644) Waxy solid. 1065. 1460. MS: EIMS (TMS) m/z 554. 353. 2928. 3 Table 4. CHCl3). 83. MeOH). uvarigin135 (C37H68O6 MW 608) Crystal. 337. 155. 1660. 2862. 363. 343. CHCl3). uvaribonin*134 (C39H70O8 MW 666) Invited Review Waxy solid. NMR: 1H NMR (500 MHz. 1470. 109. 1755. 2915. . 552. 345. CDCl3). 62. 83. acetonide (1H NMR). NMR: 1H NMR (500 MHz. CHCl3). cm-1): 3450. Vol. Derivatives: TMS (EIMS). Mp: 85-86 °C. IR (νmax.02. 371. cm-1): 3480. 570. [R]D: +13° (c 0. CDCl3). 391. 397.11. NMR: 1H NMR (500 MHz. 137. No. 13C NMR (125 MHz. bark. IR (νmax. 3677. 526. CDCl3). 321. roots. 1725. 467. 269. Derivatives: TMS (EIMS). 295. 13C NMR (125 MHz. 343. 544. 407. 111.1. 1751. 423. Source: Uvaria boniana. Derivatives: TMS (EIMS). Source: Uvaria grandiflora. 13C NMR (125 MHz. (Continued) Mono-THF Acetogenins (Continued) 70. Adjacent Bis-THF Acetogenins 73. 249. 97. [R]D: +28. 373. 2935. MW 638) Transparent oil. 267. CDCl3). 251.5° (c 0. IR (νmax. 409. CDCl3). IR (νmax. 2995. 269. 1999. cm-1): 3450. 269. CDCl3). 1745. 251. film. 181. 355. CDCl3). 293. cm-1): 3785. 1070. CDCl3). 293. 74. CDCl3). 111. IR (νmax. Derivatives: peracetate (1H NMR). 301. 2850. UV (λmax. nm): 204.526 Journal of Natural Products. 1630. Source: Annona spinescens.86). 72. 2830. 2860. 389. 339. NMR: 1H NMR (500 MHz. spinencin27 (C37H66O8. [R]D: +30. 13C NMR (50 MHz. MeOH).06. 251. seeds. 275. Source: Uvaria grandiflora. bark. MS: EIMS (TMS) m/z 562.5° (c 0. MeOH. 1760. 269. 13C NMR (125 MHz. roots. film. 311.6 (log 3. 181. Mp: 30-33 °C. cm-1): 3445. 339. 71. 295. 251. [R]D: +13° (c 0. 391. Derivatives: TMS (EIMS). 355. NMR: 1H NMR (400 MHz. 199. 409. 111. Source: Uvaria boniana. Mp: 50-52 oC. CDCl3). 2930. film. uvarigrandin A135 (C37H66O7 MW 622) Waxy solid. 97. 321. MS: EIMS (TMS) m/z 588. film.06. 373. [R]D: +24° (c 0. film. 1742. 199. 1325. 319.

Derivatives: peracetate (1H NMR).4 × 10-1.4-cis)-9-hydroxyasimicinone . 1753. 251. 13C NMR (50 MHz. Vol. VERO KB ED50 2 × 10-3. cm-1): 3677. (2. 13C NMR (50 MHz. 9-hydroxyasimicinone42 (reported as a cis and trans mixture) (C37H66O8. 62. 1749. Biological activities (µg/mL): A-549 ED50 3. film. Source: Annona spinescens. 78. film. CDCl3). MW 622) Transparent oil. VERO ED50 3. 1458. nm): 205 (log 4. 319. CHCl3). 269. Derivatives: per-MTPA esters (1H NMR). PC-3 ED50 3. CDCl3). CHCl3). CHCl3). formal acetal (1H NMR). MW 622) Transparent oil. 1999. carolin B*28 (C37H66O7. CDCl3). 3575. seeds. UV (λmax. A-498 ED50 8. cm-1): 3675. [R]D: +5° (c 0. carolin C*28 (C35H62O7. 1625.5. [R]D: +8° (c 0. MW 594) Transparent oil. mucoxin*9 (C37H67O7. CDCl3). NMR: 1H NMR (400 MHz. HT-29 ED50 6. IR (νmax. IR (νmax. MCF-7 ED50 3. MW 622) Colorless oil. MW 638) 79. 77. Biological activities (µg/mL): KB ED50 2 × 10-4.3 × 10-1. Source: Annona spinescens. Source: Rollinia mucosa.6).1 × 10-1. CDCl3). IR (νmax. Biological activities (µg/mL): KB ED50 5 × 10-6. leaves. 13C NMR (125 MHz. UV (λmax. 249. nm): 208 (log 3. carolin A*28 (C37H66O7. NMR: 1H NMR (400 MHz. MeOH. CDCl3). seeds.1 × 10-1. Derivatives: per-acetate (1H NMR). 197.Invited Review Table 4. NMR: 1H NMR (400 MHz. 267.6).7 × 10-3. nm): 208 (log 4. 3474. UV (λmax. PACA-2 ED50 3.5. 13C NMR (50 MHz.7 × 10-3. MeOH.6 × 10-2. No. 1619. 3 527 Adjacent Bis-THF Acetogenins (Continued) 75. Derivatives: peracetate (1H NMR).0). 1751. 2479. VERO ED50 5 × 10-2. Source: Annona spinescens. [R]D: +22° (c 1. TMS (EIMS). 1652. (Continued) Journal of Natural Products. cm-1): 3657. MeOH. 76. film. MS: EIMS m/z 337. CDCl3). Biological activities (µg/mL): KB ED50 1 × 10-7. seeds. CDCl3). NMR: 1H NMR (500 MHz.

PACA-2 ED50 1.20. Source: Annona glauca. 379. seeds. 141. IR (νmax. NMR: 1H NMR (200 MHz. MW 638) Transparent oil. UV (λmax. 1320. 317. 435. 3 82.94). cm-1): 3447. 519. CDCl3). CDCl3). 2930. 13C NMR (50 MHz.6 × 10-2. NMR: 1H NMR (200 MHz. MeOH. 1754. 167. 2930. 1515. CDCl3). 1464. Derivatives: peracetate (1H NMR). PC-3 ED50 1. (Continued) Adjacent Bis-THF Acetogenins (Continued) 80. 1999. 291. 251. A-498 ED50 3. MW 638) Solid. 403. No. 1745. 361. 269. nm): 219 (log 3.6 × 10-1. [R]D: +23° (c 0. IR (νmax. 263.5 × 10-1. cm-1): 3349. 1066. MeOH). 483. MS: EIMS m/z 421. 209. 339.26. NMR: 1H NMR (500 MHz. 245. 141. 118 (C H O .00). MCF-7 ED50 1. 1069. 181.3° (c 0. Biological activities (µg/mL): BST LC50 3. 465. UV (λmax. 495. 281. MS: EIMS m/z 227. HT-29 ED50 1. MeOH). cm-1): 3460. [R]D: +11° (c 0. 321. 10-hydroxyglaucanetin*117 (C37H68O8. 13C NMR (50 MHz. 2927. 255. atemotetrolin*118 (C37H67O8. 273. 97. MeOH. 317. MeOH. 379. 247. 1769. NMR: 1H NMR (200 MHz. 141. cm-1): 3423. bulladecin* 37 67 8 White solid.4-trans)-9-hydroxyasimicinone Invited Review White wax. 97. 13C NMR (50 MHz. Derivatives: per-acetate (1H NMR). 333. nm): 203 (log 2. CDCl3). Vol. 2857. film. acetonide (1H NMR). 501. 1714. MeOH. A-549 ED50 7. 2933. 123. TMS (EIMS). CDCl ). CH2Cl2). seeds. 283. Source: Annona atemoya. 431. MW 622) Solid. 1652. MeOH). film. CDCl ).54). MW 622) . 269. 81. IR (νmax. film. Derivatives: per-MTPA esters (1H NMR). TMS (EIMS).2 × 10-3. Derivatives: peracetate (1H NMR). UV (λmax. [R]D: +19. 291. 205. Derivatives: peracetate (1H NMR). MS: EIMS m/z 567. 1320. Source: 3 3 Annona glauca. 1756. 335. 149. acetonide (1H NMR).20. 417. 237. 2859. nm): 210 (log 4. 399. 1463. 321. 309. 1458. Source: Annona squamosa. nm): 209 (log 3.23. 97. 199. 385. 2851.20.98). CDCl ). [R]D: +17° (c 0.4. 171. [R]D: +15° (c 0. CDCl ). 3 Table 4. film. 533. NMR: 1H NMR (200 MHz.85). 3 3 Source: Annona atemoya. 185. stem bark. nm): 214 (log 4. 241. 101. 365. seeds. MeOH. MW 638) 83. trilobacinone119 (reported as a cis and trans mixture) (C37H66O7. 62. UV (λmax. CDCl3).7 × 10-4.7 × 10-2. MeOH). (2.528 Journal of Natural Products. 351. CDCl ). 265. 1204. MS: EIMS m/z 449. 361. 13C NMR (50 MHz. IR (νmax. 13C NMR (125 MHz. seeds. UV (λmax. MS: EIMS m/z 387. 84. glaucanetin*117 (C37H66O7. 347. 413.

1032.1 × 10-1. CDCl3). TMS (EIMS). Source: Asimina triloba. 2859. 1020. 403. 141.50).27.9 × 10-1. NMR: 1H NMR (500 MHz. Biological activities (µg/mL): 3 BST LC50 2. 557. NMR: 1H NMR (200 MHz. NMR: 1H NMR (200 MHz. Biological activities (µg/mL): A-549 ED50 1. 333. 1116. No. 1674. (Continued) Journal of Natural Products.Invited Review Table 4.6° (c 0. MS: EIMS m/z 409. 263. 1674. PACA-2 ED50 6. 1372. CDCl3). 1170. 223. MCF-7 ED50 1. 319. RPMI-7951 ED50 10-3. TMS (EIMS). HT-29 ED50 5. 291. MS: CIMS (methane) m/z 611. 88.0. Biological activities (µg/mL): A-549 ED50 6 × 10-3. 1300.9. 575. 521. 2923. CDCl3). 241. cm-1): 3450. Source: Rollinia mucosa.50). 1071. 62. stem bark. IR (νmax. 97. cm-1): 3345. 123. 369. 1450. film. CDCl3). 2923. MCF-7 ED50 1. 385.3° (c 0. 1068. TMS (EIMS). 439. Mp: 41-42 °C. 243. CDCl ). 2936. CDCl3). Mp: 42-43 °C. 463. Source: Annona atemoya. 753. film. 1079. 263. [R]D: +17. 1591. 293. 223. MW 578) White waxy solid. Source: Annona crassiflora. 1748. 453. 407. cm-1): 3432. 2845. PACA-2 ED50 1. 13C NMR (125 MHz. 315. leaves. (2.9 × 10-1. seeds. MeOH. 1436. 379. articulin30 (C37H66O8. 1742. UV (λmax.22.8. 171. 195. MeOH. cm-1): 3345. CDCl3). Derivatives: per-MTPA esters (1H NMR). 309. 1403. A-498 ED50 4. film. NMR: 1H NMR (500 MHz. nm): 222 (log 3. IR (νmax. HT-29 ED50 6 × 10-1.1. 313. 383. film. [R]D: +30° (c 0. 311. Biological activities (µg/mL): A-549 ED50 5. 141. 87. PACA-2 ED50 1. 539. 269. 1600. 1722. NMR: 1H NMR (500 MHz. CHCl3). 223. 141. A-549 ED50 4. 241. 957.9 × 10-2. 2850. HT-29 ED50 1. PC-3 ED50 1. (2. 333. 337. MS: EIMS m/z 467. CDCl3). 281. 1060. 3 529 Adjacent Bis-THF Acetogenins (Continued) 85. 141.3 × 10-8. A-498 ED50 4. 351.4-trans)-trilobacinone White wax. 89. Vol. MW 610) White solid. 13C NMR (50 MHz. 13C NMR (125 MHz. IR (νmax. 13C NMR (50 MHz. film. UV (λmax.4. 1741. MS: EIMS (TMS) m/z 523. Source: Rollinia mucosa. CDCl3). seeds. 123. IR (νmax. CHCl3). MCF-7 ED50 4 × 10-3. MeOH). nm): 222 (log 3. MS: EIMS m/z 437. IR (νmax. 111. [R]D: +9. 2859. HT-29 ED50 6. 2840. CDCl3).3. 1456. 433. 1361. 2936.6. 920. 449.4. 1750. 293. 379. 1999. U-251 ED50 10-2. 369. 397. rollidecin C55 (C35H62O6.6 × 10-4. 241. 90.3 × 10-2. leaves. PC-3 ED50 2. rollidecin D55 (C37H66O6.0. 421. Derivatives: peracetate (1H NMR).9.20. 593. 293.4-cis)-trilobacinone 86. 369. 1121. 13C NMR (125 MHz. MW 606) White waxy solid. MCF-7 ED50 5. annonisin120 (C35H62O8.363. 309. 141. PC-3 ED50 2. cm-1): 3354. MeOH. 1071. . 2920. Derivatives: peracetate (1H NMR). 1741. UV (λmax. 245. 123. EIMS m/z 403. 281. 171. MW 638) Solid.90). A-498 ED50 1. nm): 209 (log 3.0 × 10-2.0. 385.

UV (λmax. 489. CHCl3). nm): 222 (log 3. CDCl3).5. 1731. 361.5.1.54). 1999. CHCl3).7° (c 0. leaves. 173. MS: EIMS (TMS) m/z 753. 1079. A-498 ED50 1. cm-1): 3382. MeOH. glabracin A24 (C37H68O7. 293.0. (Continued) Adjacent Bis-THF Acetogenins (Continued) 91. PC-3 ED50 1. 93.1.3 × 10-1. 311. 1071. Source: Annona glabra. HT-29 ED50 1. 449. 2924. film. CHCl3). A-549 ED50 1. NMR: 1H NMR (500 MHz. 2926. cm-1): 3348. 181. MW 638) Invited Review White waxy solid. rollitacin121 (C37H68O8. leaves. 327. A-549 ED50 4. 269.5 × 10-4. Derivatives: per-MTPA esters (1H NMR).6 × 10-2.1. 1456. 397. 1064. Biological activities (µg/mL): BST LC50 3. 171. film. 171. 2919. 13C NMR (125 MHz. PACA-2 ED50 1. PACA-2 ED50 2.62. cm-1): 3330. 13C NMR (125 MHz. 1748. CDCl3). 205. MCF-7 ED50 2. 758. 2854. 1670. 289. 413.0. 92. 223. UV (λmax. IR (νmax. 1668. A-549 ED50 1.8. A-498 ED50 1.6. 956. TMS (EIMS).013. 431. CDCl3). 1747. 329. MeOH. MCF-7 ED50 4. Derivatives: formal acetal (1H NMR).8 × 10-3. PACA-2 ED50 2.1 × 10-1. Vol.05. 199. MeOH. 1318. 275.2 × 10-6. Biological activities (µg/mL): BST LC50 1. 13C NMR (125 MHz.9 × 10-2. Biological activities (µg/mL): BST LC50 3. leaves. HT-29 ED50 5. 1540.8 × 10-1. 291. 2938. MW 594) Oil. NMR: 1H NMR (500 MHz. 327. glabracin B24 (C37H68O7.2. film. 205. MS: EIMS m/z 395. 1270. 309.0. 94. MS: EIMS m/z 467. . 1203.530 Journal of Natural Products. CDCl3). 379. 379. UV (λmax. [R]D: +15. MW 638) White waxy solid. PACA-2 ED50 3. 307. film.6 × 10-1. MeOH. Biological activities (µg/mL): BST LC50 4.6 × 10-3.6 × 10-1. rollinacin121 (C35H62O7. 377. [R]D: +16. Source: Annona glabra. 449. 1469. PC-3 ED50 1. 309. 1199. nm): 223 (log 3. 223. leaves. Source: Rollinia mucosa. CDCl3). IR (νmax. 141. Derivatives: per-MTPA esters (1H NMR). 311. NMR: 1H NMR (500 MHz.89). CDCl3). MW 638) White wax solid. IR (νmax.6° (c 0. 241. UV (λmax. Derivatives: formal acetal (1H NMR). nm): 222 (log 3.58). MCF-7 ED50 1. 241. PC-3 ED50 1. TMS (EIMS). 361. 123. 141. 1320. 1717. 141. MCF-7 ED50 1. NMR: 1H NMR (500 MHz.5. 241. IR (νmax. 507. A-498 ED50 1. 325.3 × 10-1. 367. 431.52).6.8 × 10-6. 293. A-498 ED50 1. HT-29 ED50 2.9° (c 0. cm-1): 3446. 2850. 365. HT-29 ED50 4. 1072. 275. 223. 399. [R]D: -11. 1743. 205. MS: EIMS m/z 467. No. 397.7 × 10-6. 62. 3 Table 4. 13C NMR (125 MHz. A-549 ED50 2. PC-3 ED50 2. Source: Rollinia mucosa. CDCl3). CDCl3). nm): 220 (log 3.4. 663. 413. 291.

353. 335. Derivatives: acetonide (1H NMR). PC-3 ED50 3. UV (λmax. CDCl ). 465. 83. A-498 ED50 1. 489. MeOH). 13C NMR (125 MHz. 241. MW 638) Pale yellow wax. 1215. 347. 415. NMR: 1H NMR (400 MHz. 1215. [R]D: +20° (c 1. 461.343. 111. 1028. [R]D: +17. CDCl3). 1750. 101. purpurediolin123 (C37H66O8. 223. 62. seeds. 455. 1375. 3023. 123. film. cm-1): 3650. 151. 1203. 265. 473. 1467. 585. NMR: 1H NMR (500 MHz. 501. 927.1. 247. Source: Rollinia membranacea. 283. MeOH. 519. 153.3. Biological activities (µg/mL): BST LC50 2. CDCl3). 97. nm): 210 (log 3.23. 2924. UV (λmax. 465. CDCl ). 641. IR (νmax.4. purpurenin123 (C37H66O8. HT-29 ED50 < 10-7. 483. 3021. nm): 218 (log 4.5° (c 0. Mp: 63.Invited Review Table 4. 173. 173. 1652. MeOH. MeOH). UV (λmax. PC-3 ED50 1. cm-1): 3430. 293. 417. 83. film. 1641. 1118. . cm-1): 3100-3700. 307. NMR: 1H NMR (600 MHz.7. A-498 ED50 1. 289. Vol. 1324. film. TMS (EIMS). formal acetal (1H NMR). 13C NMR (150 MHz. MS: EIMS (TMS) m/z 753.95). 185. 73. Source: Uvaria microcarpa. No. 309. 277. 399.4. 930. PACA-2 ED50 2. 417. Derivatives: peracetate (1H NMR). 83. 13C NMR (100 MHz. 241. per-MTPA esters (1H NMR). microcarpacin36 (C37H66O8. 325. 1749. 1462. MW 638) White waxy solid. 167. 722. CDCl3). 435. MW 638) White wax. MCF-7 ED50 1. 111.89). 1074.9 × 10-2.2 × 10-1. 1316. 663. 2849.4° (c 0. UV (λmax. 297. 423. TMS (EIMS). Mp: 35-39 °C. 1999. MeOH. 3 3 96. MCF-7 ED50 9. seeds. 2859. 141. 447. rollimembrin122 (C35H62O7. 675. 507. MS: EIMS m/z 537. MeOH. MS: EIMS (TMS) m/z 765. 203. 73.09). 399. 2940. 505. 137. 98. [R]D: +12. 551. Mp: 36-38 °C.3. MW 594) White amorphous solid. 1751. 13C NMR (125 MHz. 311. PACA-2 ED50 1. 2922. 1200.0 × 10-2. 155. nm): 208 (log )4.2 × 10-1. 731. seeds. 3 531 Adjacent Bis-THF Acetogenins (Continued) 95. CDCl3). [R]D: +27° (c 1. 2928. CDCl3). per-MTPA esters (1H NMR). (Continued) Journal of Natural Products. IR (νmax. 1070. Source: Annona purpurea. film. 491. 916. 275. 495. 173. A-549 ED50 1. 331. 149.5-65 °C. Biological activities: NADH oxidase IC50 0. 437. 595. IR (νmax. 365. 509. 1428. 1647. 107. Biological activities (µg/mL): BST LC50 7.0. A-549 ED50 4. NMR: 1H NMR (500 MHz. CDCl3). 573. 111. cm-1): 3383.0. 265. seeds. MeOH).07). Source: Annona purpurea. 317. 949.5 × 10-1. 871. 1642. nm): 207 (log 3. 429. MeOH). 1423. MS: EIMS m/z 483. 111.33 nM. 367. HT-29 ED50 3. 1075. Derivatives: per-MTPA esters (1H NMR).3. 483. IR (νmax.4 × 10-1. 1751. 295.4.

cm-1): 3350.0 × 10-1. NMR: 1H NMR (400 MHz. 345. A-498 ED50 >1. uvariasolin II*37 (C37H66O8.532 Journal of Natural Products. CDCl3). MCF-7 ED50 3. 247. 317. 62. TMS (EIMS). 205. 13C NMR (50 MHz. 489. 1455. 333. 137. IR (νmax.3° (c 0. 275. stem bark. 363. MW 638) Colorless wax. NMR: 1H NMR (400 MHz. Biological activities (µg/mL): BST LC50 4. film. MS: FABMS m/z 645. 473. Source: Uvaria pauci-ovulata. 121.22. 489. 1359. cm-1): 3376. 1740. [R]D: +17. MW 638) White waxy solid. . 2922. PC-3 ED50 >1.6 × 10-1. CDCl3). stem bark. film. 317. CHCl3). TMS (EIMS). 473. A-549 ED50 3. NMR: 1H NMR (400 MHz. stem bark. CDCl ). 2856. (Continued) Adjacent Bis-THF Acetogenins (Continued) 99. 519. 1594. 275. 317. 361. Source: Uvaria pauci-ovulata. CDCl ). 1600. 13C NMR (125 MHz. CDCl ). per-MTPA esters (1H NMR).5 × 10-1. HT-29 ED50 3. 1999. A-498 ED50 >1. 160. 13C NMR (125 MHz. 3 101. A-549 ED50 6. MW 638) Invited Review White waxy solid. 1074.3° (c 0. uvariasolin I*37 (C37H66O8. 13C NMR (50 MHz. espelicin*37 (C37H66O8. MS: FABMS m/z 519. 457. 487.1 × 10-1. 333. 1103. Source: Uvaria pauci-ovulata. 1125. bullatetrocin124 (C37H66O8. 415. 154. 247. 221. 403. [R]D: +16. 431. NMR: 1H NMR (500 MHz. 627. PC-3 ED50 5. 136. CHCl3). Source: Asimina triloba. 361. 2923. 291. Source: Asimina triloba. CDCl3). MCF-7 ED50 5. CDCl3). MW 638) Colorless wax. 489.3 × 10-1. 103. 1742. 1116. 2846. CDCl3). 1467. Derivatives: peracetate (1H NMR). PACA-2 ED50 >1. No. MW 638) White waxy solid. 333.3 × 10-1. stem bark. acetonide (1H NMR).7 × 10-1. Vol. 459. 10-hydroxyasimicin124 (C37H66O8. per-MTPA esters (1H NMR). HT-29 ED50 7. 161.27. MS: FABMS m/z 519. Derivatives: peracetate (1H NMR). 100. 205. NMR: 1H NMR (500 MHz. 459. IR (νmax. 431. 387. Biological activities (µg/mL): BST LC50 3. 403. 1318. PACA-2 ED50 >1. CDCl3). CDCl ). 13C NMR (50 MHz. stem bark.3 × 10-1.3 × 10-1. 3 102. 3 3 acetonide (1H NMR). 3 Table 4.

(Continued) Journal of Natural Products. cm-1): 3365. 2925. (2. IR (νmax. 275. per-MTPA esters (1H NMR). 283. A-498 ED50 4. 2856. bullacin125 (C37H66O7. CDCl ). per-MTPA esters 3 3 (1H NMR). nm): 203 (log 3. 2921. MeOH.0 × 10-8. 3 533 Adjacent Bis-THF Acetogenins (Continued) 104.03.0 × 10-1. 359.7 × 10-3. 151. 415. NMR: 1H NMR (500 MHz. PC-3 ED50 >1.4. HT-29 ED50 1. HT-29 ED50 4. UV (λmax. 397. 2851. 345.0 × 10-3. PACA-2 ED50 4. 13C NMR (125 MHz. CDCl3). 2850. 341. A-498 ED50 1. 1036. PACA-2 ED50 1. PACA-2 ED50 1. 2920.9 × 10-8. cm-1): 3418. CDCl3).0 × 10-2. A-549 ED50 1. PC-3 ED50 1. 1120. 1770. 13C NMR (125 MHz.3° (c 0. A-498 ED50 >1. squamolinone125 (reported as a cis and trans mixture) (C35H62O7. 1999. 10-hydroxytrilobacin124 (C37H66O8. MCF-7 ED50 2.4-trans)-squamolinone White amorphous powder. 325. 1420. Biological activities (µg/mL): BST LC50 2.6.4° (c 0. 2928. nm): 211 (log 3. MW 638) Colorless oil. Source: Asimina triloba.6 × 10-1.8 × 10-1.9 × 10-2.4 × 10-2.8. HT-29 ED50 4. CHCl3). (2. Biological activities (µg/mL): BST LC50 1. PACA-2 ED50 2. IR (νmax. MCF-7 ED50 2. Biological activities (µg/mL): BST LC50 7. HT-29 ED50 1.79). Source: Annona squamosa.1. A-549 ED50 1. film. 13C NMR (125 MHz.7. film.4-trans)-9-oxoasimicinone White amorphous powder. MS: EIMS m/z 377. CH2Cl2). MS: EIMS m/z 363. A-549 ED50 9. formal acetal (1H NMR). A-549 ED50 5. NMR: 1H NMR (500 MHz. [R]D: +21. MW 636) 107. 289. . [R]D: +8. CDCl3). Derivatives: peracetate (1H NMR). nm): 203 (log 2. 169.2.85).1 × 10-1. MS: EIMS m/z 433. NMR: 1H NMR (500 MHz.5 × 10-7.073.8. 307. stem bark. 345. Derivatives: peracetate (1H NMR). Derivatives: per-MTPA esters (1H NMR). 1767. stem bark. 293. 363. Vol. CDCl ). cm-1): 3390. PC-3 ED50 2. CDCl ). 1705.4-cis)-squamolinone 106.7 × 10-1. 1756. Derivatives: per-MTPA esters (1H NMR).6 × 10-1. UV (λmax. PC-3 ED50 3. 311.7° (c 0. NMR: 1H NMR (500 MHz. 1590. 1456. A-498 ED50 1. 109. CH2Cl2). No. [R]D: +43. stem bark. IR (νmax. MCF-7 ED50 1. 3 TMS (EIMS). MCF-7 ED50 1. CDCl3).1.9. film.10. (2. Source: Annona squamosa. MeOH.36.5 × 10-3. MW 594) 105.0 × 10-7. film. Biological activities (µg/mL): BST LC50 6.Invited Review Table 4. 2853. MeOH. 13C NMR (125 MHz. CHCl3). 9-oxoasimicinone125 (reported as a cis and trans mixture) (C37H64O8. UV (λmax. CDCl3). MW 622) White amorphous powder. cm-1): 3426. [R]D: +19. Source: Annona squamosa. IR (νmax. 1752.6 × 10-1.8° (c 0. 207. 62.4-cis)-9-oxoasimicinone 108. TMS (EIMS).55). 311. acetonide (1H NMR). 327. (2. stem bark. 225.

1066. 281. 1647. EIMS m/z 425. Source: Goniothalamus giganteus. A-549 ED50 3. film. film. 495. IR (νmax.6 × 10-1. No. 13C NMR (100 MHz. 1456. [R]D: +10° (c 0. 245. 311. 113. Biological activities: NADH oxidase IC50 0.3 × 10-2. MCF-7 ED50 3. 291. PC-3 ED50 9.6° (c 0.7.8 × 10-1. CHCl3). cm-1): 3416. 542. 365. MW 636) White wax. nm): 208 (log 3. 1066.0° (c 0. Biological activities: NADH oxidase IC 3 50 1.95). 1751. PC-3 ED50 2. 13C NMR (125 MHz. 390. Biological activities (µg/mL): BST LC50 5. CDCl3). 1039. PACA-2 ED50 2. Source: Rollinia membranacea. 313. 13C NMR (125 MHz.125. 171. 141.6 × 10-7. 1456. 1750. stem bark. 405. CDCl ). stem bark. 319. 3 Table 4. trilobalicin*119 (C35H62O8. 407. 223. 311. NMR: 1H NMR (400 MHz. CDCl3). 1718. NMR: 1H NMR (500 MHz. IR (νmax. 241. CDCl3). 97. CDCl3). CDCl3). 197.5 nM. 1116. MeOH). 371. MS: EIMS m/z 449. 13C NMR (100 MHz. 1398. Vol.3 nM. 2940. 361. HT-29 ED50 1. 455. 2922. [R]D: +22° (c 1. 213. Derivatives: per-MTPA esters (1H NMR). film. 111. seeds. membrarollin137 (C35H62O6 MW 578) Invited Review White wax. A-549 ED50 5. 195. 389. 1738. Biological activities (µg/mL): BST LC50 2. A-498 ED50 6. 337. IR (νmax. MW 610) White wax.3. 293. 223.8 × 10-8. Derivatives: per-MTPA esters (1H NMR). 267. guanaconne138 (C37H64O7 MW 620) Colorless wax. 601. cm-1): 3333. 111. 345. 407. cm-1): 3370. p-bromophenylurethane (1H NMR). 2925. nm): 210 (log 3. 619.4. 436. 545. MeOH. 62. [R]D: +13. 2880. [R]D: +10. 583. 560. (Continued) Adjacent Bis-THF Acetogenins (Continued) 110.3 × 10-5. 337. Source: Asimina triloba. 241. 263. Derivatives: per-MTPA esters (1H NMR). 263. EtOH). NMR: 1H NMR (500 MHz.8. MS: EIMS m/z 578. 379. 353. 275. UV (λmax.534 Journal of Natural Products. cm-1): 3378. MCF-7 ED50 1. 381. 339. MS: CIMS (isobutane) m/z 637. A-498 ED50 1. MW 638) . MS: EIMS m/z 585.363. goniotriocin*39 (C37H65O8. 153.03. gigantecinone126 (reported as a cis and trans mixture) (C37H66O8. 2853. film. IR (νmax. Source: Annona spraguei. Derivatives: per-MTPA esters (1H NMR). 1750.83).1. NMR: 1H NMR (400 MHz. TMS (EIMS). 321.2 × 10-3.0 × 10-3. CHCl3).8 × 10-1. 1594. seeds. MeOH. 1999. CDCl3). 2866. 1548. 1458. HT-29 ED50 2. CDCl3). 223.8. UV (λmax. 1380. PACA-2 ED50 1. Nonadjacent Bis-THF Acetogenins 112. 2919. 309.

1650. muridienin-2128 (C37H66O2. 13C NMR (125 MHz.4-trans)-gigantecinone White wax.307. 367. IR (νmax. IR (νmax. 34-epi-donnaienin D White amorphous powder. Mp: 78-81 °C. 289. Derivatives: peracetate (1H NMR). 199. 351. 1468. 141. NMR: 1H NMR (500 MHz.1. 307.1 × 10 50 1.4-cis)-gigantecinone 115. nm): 211. 2900. A-549 ED50 2. cm-1): 3300. CDCl ).Invited Review Table 4. A-498 ED50 -1. Non-THF or THP Acetogenins 116.1 × 10 . 413. 1080. 269.21. MW 542) donnaienin D34 (reported as an epimeric pair) (C37H66O9. 349. montecristin127 (C37H66O4. 3 535 Nonadjacent Bis-THF Acetogenins (Continued) 114. Vol. CDCl3). 1708.3. MCF-7 ED50 >1. 269.6° (c 0. film. 385. (Continued) Journal of Natural Products. 3 Biological activities (µg/mL): BST LC50 3. per-MTPA esters (1H NMR). CHCl3). NMR: 1H NMR (500 MHz. 62. (2. 1461. MeOH). Biological activities (µg/mL): KB IC50 >10. CHCl3). HCT-8 IC50 >10. 1190. [R]D: +23. [R]D: +25° (c 0. 359. 341. cm-1): 3507. 1999. 139. 369. Source: Annona muricata.7 (log 3. 333. CDCl3). Source: Goniothalamus donnaiensis.1 × 10-1. Derivatives: phenylhydrazone (1H NMR). PC-3 ED -3 2. 251. 303. 1751.15. MS: EIMS m/z 473. . 403. 13C NMR (125 MHz. 1740. donnaienin D 120. 421. 2837. Derivatives: acetonide (1H NMR). 2918. MW 672) 119. PACA-2 ED50 >1. MW 514) 118. UV (λmax. formal acetal (1H NMR). 1749. stem bark. HT-29 ED50 >1. 1167. Mp: 62-65 °C. 2908. 3389. Source: Goniothalamus giganteus. muridienin-1128 (C35H62O2. 13C NMR (50 MHz. No. film.80). 2840. NMR: 1H NMR (400 MHz. 281. cm-1): 3360. 339. 395. 321. roots. 1120. film. Bel IC50 >10. IR (νmax. 199. CDCl3). 2849. 1030. MS: EIMS m/z 439. CDCl3). 325. 263. 121.3° (c 0. CDCl3). 1049. 377. acetonide (1H NMR). MW 574) White wax. roots. [R]D: +8. MeOH. per-MTPA esters (1H NMR). (2. 117. 287. 251.

MeOH). No. 321. CDCl3). 295. 3 Table 4. chatenaytrienin-129 (reported as a mixture of chatenaytrienins 1 and 2) (C35H60O2. 1090. 403. 167. 323. MW 512) . 249. 209. fruits. 279. MeOH. 417. 715. 97. 1470. 111. 123. nm): 210 (log 3. 1020. 351. cm-1): 330. 111. MW 548) Powder. 468. cm-1): 3300. 13C NMR (50 MHz. 1190. 1760.2 (log 2. Source: Annona muricata. IR (νmax. 141.5. 111.5. 1650. Source: Rollina mucosa. 1090.90). 2860. 349. CHCl3). 1080. (Continued) Non-THF or THP Acetogenins (Continued) 121. 1470. 524. 468.90). 249. MeOH. CHCl3). Mp: 60-62 °C. 265. 295. 209. 1310. film. 97. Derivatives: acetonide (1H NMR). cohibin A130 (C35H64O4. 124. 321. 1310. 141. MS: EIMS m/z 548. 111. 2840. 1120. 13C NMR (100 MHz. 295. 1740. 1999. MeOH). CDCl3). 1760. 1650. 1120. nm): 212. cohibin B130 (C35H64O4. cm-1): 2910. [R]D: +12° (c 0. CDCl3). MS: EIMS m/z 539. 167. NMR: 1H NMR (400 MHz. fruits.2 (log 2. nm): 210 (log 3. film. epomusenin A129 (C37H67O4. Derivatives: acetonide (1H NMR). 265. 112. CDCl3). Mp: 60-62 °C. 2900. MeOH. 349. UV (λmax. MW 548) Powder. 524. 368. NMR: 1H NMR (400 MHz. UV (λmax. [R]D: +24° (c 0. MW 558) Invited Review Waxy solid. Source: Annona muricata. 2900. roots. IR (νmax. 279. nm): 212.1. 2860. epomusenin B129 (C37H67O4. film. UV (λmax. [R]D: +24° (c 0. 2840. IR (νmax. 351. 1030. IR (νmax. CDCl3). [R]D: +12° (c 0. CDCl3). 1460.1.82). CDCl3). MS: EIMS m/z 539. 125. NMR: 1H NMR (400 MHz. 368. 1740. 237. 417. NMR: 1H NMR (400 MHz.82). 237. MS: EIMS m/z 548.536 Journal of Natural Products. 112. 1190. 1030. 97. 267. 1460. cm-1): 2910. 231. Source: Rollina mucosa. UV (λmax. 62. film. 122. MW 558) Waxy solid. 1020. 13C NMR (50 MHz. 13C NMR (100 MHz. roots. 715. 97. CDCl3). MeOH. 1080. 277. Vol.

139. longanin131 (C35H66O5. 2845.85.2 × 101.18. Source: Annona nutans. MeOH. CDCl3). UV (λmax. 195. Source: Annona nutans. 209. CDCl3). Biological activities (µg/mL): BST LC50 1. nm): 214.9 × 10-2. . MCF-7 ED50 3. CDCl3). MS: EIMS m/z 295. seeds. 13C NMR (50 MHz. MW 540) Oil. IR (νmax. 129. Source: Asimina longifolia. MW 566) Colorless wax. 13C NMR (125 MHz. nm): 214. NMR: 1H NMR (200 MHz. 153. cm-1): 2929. MW 574) White wax. MW 512) Oil. CDCl3).0 × 10-1. roots. CDCl3). 251. CDCl3). PACA-2 ED50 1. A-549 ED50 4. CDCl3). 1745. IR (νmax. Vol. CHCl3). NMR: 1H NMR (400 MHz. 167. chatenaytrienin-429 (reported as a mixture of chatenaytrienins 3 and 4) (C37H66O2. 97. 125. 62. 13C NMR (50 MHz. MS: CIMS m/z 541. 127. 755.9 × 10-2. [R]D: +25° (c 0. MeOH.0 × 10-1. Derivatives: TMS (EIMS). diepoxyrollin132 (C37H66O4. 181. 1761. chatenaytrienin-229 (reported as a mixture of chatenaytrienins 1 and 2) (C35H60O2. nm):208. No. 265. MeOH. UV (λmax. leaves and twigs. 237.Invited Review Table 4. film. A-498 ED50 3. CDCl3). MW 540) 128. 2857. 223. 111. (Continued) Journal of Natural Products. roots. MS: EIMS (TMS) m/z 299.1 × 10-2. Source: Rollinia membranacea. 1657. CHCl3). film. 295. NMR: 1H NMR (500 MHz. [R]D: +11° (c 0. cm-1): 2910. HT-29 ED50 6. MS: CIMS (isobutane) m/z 513. 130.4. 1999. 13C NMR (50 MHz. NMR: 1H NMR (400 MHz. chatenaytrienin-329 (reported as a mixture of chatenaytrienins 3 and 4) (C37H66O2. PC-3 ED50 4. UV (λmax. 3 537 Non-THF or THP Acetogenins (Continued) 126.

cm-1): 3360. film. [R]D: +14.9 × 10-1. film. 1199. nm): 216 (log 3. 307. 1742. [R]D: +10° (c 0.07. 2897. 265. A-498 ED50 1. 209. 141. MW 546) Invited Review White wax. MeOH). Derivatives: per-MTPA esters (1H NMR). 561.538 Journal of Natural Products. IR (νmax. A-549 ED50 2. 13C NMR (125 MHz.8 × 10-1. A-498 ED50 4. CDCl3). NMR: 1H NMR (500 MHz. 319. 97.5. Biological activities (µg/mL): HL-60 IC50 1. tonkinelin133 (C37H70O4. 1999. 3 Table 4.53). 223. MW 590) Waxy solid.8 × 10-1. 2845.8 × 10-1. TMS (EIMS). PACA-2 ED50 5. Derivatives: acetonide (1H NMR). 141. PC-3 ED50 4. nm): 208. IR (νmax. 2915. pyranicin10 (C35H64O7. [R]D: +15. Biological activities (µg/mL): BST LC50 1. nm): 220 (log 3. TMS (EIMS). MeOH. CDCl3). per-MTPA esters (1H NMR). 1456. KB IC50 >10. 253. 235. root bark.9 × 10-2. HT-29 ED50 1. CDCl3). 1086.1 × 10-1. CDCl3). CDCl3). diepomuricanin B132 (C35H62O4. No. 293. 111. PACA-2 ED50 1. 1319. MS: EIMS m/z 426. [R]D: -9. Source: Rollinia membranacea. UV (λmax. 135. NMR: 1H NMR (500 MHz. Nonclassical Acetogenins 134. cm-1): 3341. stem bark. CHCl3). 269. MW 622) White wax. HT-29 ED50 3. 13C NMR (125 MHz.5° (c 0. 2848. 132.4 × 10-4. twigs.9 × 10-1. cm-1): 3400. 335. 62. . A-498 ED50 1. CHCl3). NMR: 1H NMR (500 MHz.1 × 101. 323.2. 335. MW 578) White amorphous powder. 2910. 337. MW 596) White amorphous wax. Mp: 64-66 °C. A2780 IC50 >10. CDCl3). Source: Goniothalamus giganteus. Source: Annona jahnii.75.6 × 10-2. 1282.8. Source: Uvaria tonkinesis. 1703.32). IR (νmax. 181. 1737. MeOH.7. 125. MS: EIMS m/z 323. MCF-7 ED50 3. 291. 97. 251. CDCl3). Derivatives: per-MTPA esters (1H NMR). MCF-7 ED50 2. CDCl3).9. 13C NMR (50 MHz. 153. 543. IR (νmax. CDCl3). film.5 × 10-3. PC-3 ED50 1. 133. 1469.7° (c 0. MCF-7 ED50 2. 13C NMR (125 MHz. PACA-2 ED50 2. 387. Source: Rollinia mucosa. 1748. PC-3 ED50 5. 2928. 317. UV (λmax. 2918. UV (λmax. 1648. film. HT-29 ED50 5. 1467.0° (c 0. (Continued) Non-THF or THP Acetogenins (Continued) 131. 2854. 269. leaves. 195. 309. cm-1): 3418.4 × 10-4.8 × 10-1.0.3 × 10-3. Derivatives: acetonide (1H NMR).3 × 10-2. 13C NMR (125 MHz. CDCl3). NMR: 1H NMR (200 MHz. 283.008. MS: EIMS m/z 405. NMR: 1H NMR (500 MHz.008. MS: EIMS m/z 367. 167. 139. CHCl3). A-549 ED50 1. 273. 669. 205. Biological activities (µg/mL): A-549 ED50 4. Biological activities (µg/mL): BST LC50 3 × 10-1. Mp: 70-72 °C. 241. 223. 125. seeds. muconin9 (C37H67O7. MS: EIMS m/z 579. 1745. 279. annojahnin12 (C35H66O5. HCT-8 IC50 6. 97. Vol. 353. MeOH.

F. J. A. 1997. 1997. D. R. MeOH. F. J. 3023. K. Chuah. Z. 1641. H. Am. Prod. No. J.. L.. Nat. M.. N. J. 3151-3153. J. L. Schwedler. [R]D: +8. W. Res. Bioorg. formal acetal (1H NMR). nm): 215 (log 3. 46.. 1998. F. Vol.3 × 10-1. Kirby. 321-326. G. R. H. Cave. 61. J. film. L. 339... Fourneau.. Moeschler. Kozlowski. Hopp.. L. T.. Sun. L. R. Pharmacol. Tetrahedron Lett.. Y. L. R. I. ´ L. G.. . Chen. 47. G. 1997. H... 3 539 Nonclassical Acetogenins (Continued) 136. 2783-2813. H. Harrison. (33) Jiang.. McGovern. cm-1): 3479. per-MTPA esters (1H NMR).. Sha. F. 1998. 22. D. 1994.. G. Jiang. Mata. Blazquez. Roblot. F. Y.. Farley. Phytochemistry 1997.. J.. R. A-549 ED50 1.2 × 10-1.. De ´ Arias.. L.. J. M. Y. 1997. Org. D. Q. PC-3 ED50 2. (21) Oberlies N. Roblot. T.. J. IR (νmax. 9.. L. Figadere. Mukherjee. A. (14) Lewis. R.. McLaughlin.. He. Y. R. C. D. J.-M. 141.. 1748. Linnane. 10409-10410.. A. L..97). 47.. McLaughlin.. 443-452.. Oberlies. Rogers. Roblot. Philogene. TMS (EIMS).-Y. J. 1999.. J. 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