Applied Microbiology and Biotechnology (2018) 102:4663–4674

https://doi.org/10.1007/s00253-018-8968-7

MINI-REVIEW

Naturally occurring aromatic steroids and their biological activities

Valery M. Dembitsky 1,2 & Nick Savidov 1 & Vladimir V. Poroikov 3 & Tatyana A. Gloriozova 3 & Andrew B. Imbs 2

Received: 11 February 2018 / Revised: 21 March 2018 / Accepted: 22 March 2018 / Published online: 21 April 2018
# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
The present review describes the distribution and biological activities of natural mono-, di-, and triaromatic steroids. It is
shown that the producers of aromatic steroids are microorganisms, fungi, and marine invertebrates, and also they were
found in plants, animals, marine sediments, and karst deposits. Eighty biologically active aromatic steroids likely have
an anti-tumor, anti-inflammatory, and neuroprotection activity with a confidence of 78 to 92%. The structures and
predicted biological activities of aromatic steroids are available. This review emphasizes the role of aromatic steroids
as an important source and potential leads for drug discovery and they are of great interest to chemists, physicians,
biologists, pharmacologists, and the pharmaceutical industry.

Keywords Aromatic . Steroids . Lipids . Plant . Invertebrates . Sediments . Fungi . Microorganisms

Introduction in marine sediments and oil, and less in geological samples

Aromatic steroids are lipids that contain at least one or
more aromatic ring(s) in a steroid skeleton. Aromatic ste-
roids are a fairly large group of lipids that are produced
by bacteria, plants, fungi, and animals (Kadis 1957; Taub
1973, 1984; Rutherford 1972; Niven 1999; Gupta and
Jain 2000; Dembitsky et al. 2017). In addition, natural
aromatic steroids as potential molecular fossils have been
found both in the ascomycete, as well as geological sam-
ples and marine sediments, and in oil and petroleum
(Riolo et al. 1986; Pu et al. 1990; Barbanti et al. 2011;
Yang et al. 2013; Matyasik and Bieleń 2015).
Currently, the monoaromatic steroid group is the most
widespread group of natural lipids (Lednicer 2010). This
group contains an aromatic A or B ring. Representatives
of A-aromatic ring group found more than 220 in nature,
and those of B-aromatic ring group found about 20.
Monoaromatic steroid hydrocarbons are also widely found
* Valery M. Dembitsky
valeryde@imb.dvo.ru
1
Centre for Applied Research and Innovation, Lethbridge College,
3000 College Drive South, Lethbridge, AB T1K 1L6, Canada
2
Biochemistry Lab, National Scientific Center of Marine Biology, 17
Palchevsky Str., Vladivostok, Russia 690041
3
Institute of Biomedical Chemistry, Moscow, Russia 119121
(Pu et al. 1990; Barbanti et al. 2011; Yang et al. 2013;
Matyasik and Bieleń 2015). A group of diaromatic steroids
is relatively small, and in living organisms only 25 such
lipids are found. A group of diaromatic steroids is relatively
small, and only 25 such lipids are found in living organ-
isms, although much more is found in geological samples,
in marine sediments, or in oil. For triaromatic steroid hy-
drocarbons, there are four in the living organisms, although
geological and marine sediments are widely represented, as
well as in oil (Pantoja and Wakeham 2000; Killops and
Killops 2004; Barbanti et al. 2011; Yang et al. 2013;
Matyasik and Bieleń 2015). The biological activity of aro-
matic steroids, which are found in living organisms, is
poorly studied, and the same compounds found in geolog-
ical and marine sediments have not been studied. We select-
ed 70 different aromatic steroids from 250 steroids found in
living organisms, and from more than 400 steroids that
were found in geological samples, marine sediments, and
oil. Biological activities were found for these compounds
(Pantoja and Wakeham 2000; Killops and Killops 2004).
As already proved by numerous works, there is a relation-
ship between structure and activity, and this principle is called
SAR (structure-activity relationship). We used the computer
program PASS, containing about one million chemical com-
pounds and more than 8000 biological activities, and estimat-
ed the biological activity of different natural and/or synthetic
compounds (Dembitsky et al. 2017a, b). PASS predictions are
based on SAR analysis of the training set consisting of more
4664
than one million drugs, drug candidates, and lead compounds.
The algorithm of PASS and its practical utilization are de-
scribed in detail in many publications (see, e.g., Filimonov
et al. 2014; Dembitsky et al. 2015; Levitsky et al. 2016;
Druzhilovskiy et al. 2017; Gawande et al. 2017;
Murtazalieva et al. 2017; Goel et al. 2018).
Distribution of ring A monoaromatic steroids
in plant species
Among the monoaromatic steroids, the most well known are
estrogens, such as estrone (1), estradiol (2), estriol (3), equilin
(4), hippulin (7), and their derivatives (5, 6, 8, 9; structures in
Fig. 1). Estrone is a minor female sex hormone that was dis-
covered in 1920s from the urine of pregnant women, indepen-
dently by two groups of scientists from Germany and the USA,
by biochemist Adolf Butenandt and the American scientists
Edward Doisy and Edgar Allen, respectively (Edgar and
Edward 1923; Doisy et al. 1929; Butenandt 1929, 1930,
1931; Edgar and Doisy, 1923; Fluhmann 1938). Later, Adolf
Frederick Johann Butenandt of the Institute of Chemistry in
Göttinge (Germany) received the Nobel Prize for Chemistry
in 1939 for the discovery of this hormone. Estra-1,3,5(10)-tri-
ene-3-ol-17-one (1), also known as estrone, is a naturally oc-
curring estrane steroid, which is produced in vivo from andro-
stenedione and/or testosterone via estradiol. The
abovementioned estrogens show estrogenic activity with vari-
ous variations (Younglai and Solomon 1968; Raeside 2017),
although changes in the structure of the ring of D estrogens may
also demonstrate anticancer activity (Trifunović et al. 2017).
The presence of female sex hormonal steroids (1–7) estro-
gens was first detected in plants in 1926 by Dohrn et al. (1926)
and then in the 1930s, simultaneously by Butenandt and
Jacobi (1933) and Skarzynski (1933). Recently, Janeczko
and Skoczowski (2005) published a survey in which they
summarized the data on the presence of mammalian sex hor-
mones and their physiological role in plants. These hormones,
such as 17β-estradiol, androsterone, testosterone, or proges-
terone, were present in 60–80% of the plant species
investigated.
Butenandt and Jacobi (1933) isolated estrone (1) from
seeds and pollen Phoenix dactylifera, Punica granatum,
Malus pumila, Hyphaene thebaica, Salix caprea, and
Glossostemon bruguieri. 17β-Estradiol (5) was found in the
seeds of Phaseolus vulgaris, along with estrone (1), and estriol
(3) was found in Salix sp., and Glycyrrhiza glabra.
A large-scale research on the content of sex steroids was
conducted by Canadian biologists Simons and Grinwich in
1989 using radioimmunoassay (Simons and Grinwich 1989).
Androsterone and progesterone were found in more than 80%
of the investigated species, androgens (testosterone and dihydro-
testosterone) in 70% of species, and estrogens (estrone and 17β-
Appl Microbiol Biotechnol (2018) 102:4663–4674
estradiol) in 50% of species. In addition, Zhang et al. (1991), also
using the method, estimated the content of total estrogens and
17β-estradiol in the pollen and in the style of Ginkgo biloba, Zea
mays, Brassica campestris, and Lilium davidii. Zhong-han et al.
(1994) proved the presence of testosterone in the pollen of Pinus
bungeana, Ginkgo biloba, and Pinus tabulaeformis using the
ELISA method. Testosterone was not detected in the pollen of
Juglans regia, B. campestris, and L. davidii.
A steroidal alkaloid, holaromine (10), was isolated more
than 50 years ago from the extract of an ornamental shrub
Holarrhena floribunda, native to the Congo. It is known that
the bark is known as a cure for dysentery and diarrhea. The
biological activity of this steroid has not been determined
(Janot et al. 1967).
Phytoestrogen deoxymiroestrol (11) was first reportedly
isolated from the Thai herb Pueraria mirifica in 1960 (Cain
1960). Unusual steroids called as withanolides (12, 16, and
17) were isolated from plants (Misico et al. 2011). The
jaborosalactone-7 was isolated from Jaborosa leucotricha
collected in late spring in Argentina (Misico et al. 1997),
and jaborosalactone-45 was found in Jaborosa laciniata con-
taining an aromatic ring A (Cirigliano et al. 2007). Biological
activities of these aromatic steroids have not been studied.
Andirobicin B glucoside (13) was present in the extract of
Fevillea trilobata seeds (Valente et al. 1993), and 1-methyl-
19-nor-25D-spirosta-1,3,5(10)-trien-11α-ol (14) and its ace-
tate (15) were isolated from the rhizome of Metanarthecium
luteoviride, which were collected in Shiga Prefecture (Igarashi
1961). Biological activities aromatic steroids (11–15) have not
been studied. Luvigenin (18) was isolated from the leaves of
Metanarthecium luteoviride (Minato and Shimaoka 1961),
Yucca gloriosa (Pkheidze et al. 1991), and Allium giganteum
(Sobolewska et al. 2016), and biological activity of this com-
pound has not been studied.
A family of anticancer compounds named as
cayaponosides including cayaponoside A4 (19) have been
isolated from the roots and bark of the Tayuya tree, which is
widespread in the Amazon rainforest in Brazil, Peru, and
Bolivia (Himeno et al. 1992, 1994; Konoshima et al. 1995).
The cangorosin A type triterpene dimer, xuxuasin B (20),
which is composed of two triterpene units jointed by two ether
linkages between the A and B rings, was isolated from the
Brazilian medicinal plant Bxuxuá^ (Maytenus chuchuhuasca)
(Shirota et al. 2004), and biological activity of this compound
has not been studied.
Extracts of leaves and roots of Maytenus ilicifolia (known
as BEspinheira Santa^) the people used in traditional Brazilian
medicine demonstrate anticancer activity and contained a ste-
roid 6-oxotingenol (21) (Araújo et al. 2013; Vendruscolo et al.
2005; Goncalves and Martins 1998).
Aromatic triterpenoid (22) was detected in the cones of
Taxodium balticum extract (Si et al. 2005) and was also found
among terpenoids in Eocene and Miocene conifer fossils (Otto
Appl Microbiol Biotechnol (2018) 102:4663–4674 4665

O OH OH O

H H H OH

A H H H H H H H H

HO HO HO HO

1 Estrone 2 Estradiol 3 Estriol O 4 Equilin

OH
OH
O

H
H H H
H H
HO HO
HO
HO 7 Hippulin
6 8,9-Dehydroestradiol
5 17 -Dihydroequilin 8 16,17-Epoxyestra-1,3,5(10)-trien-3-ol
N
OH H OH
H
OH
H
H OH
H

O O
H H
OH H
H OH
O OH
HO
HO O

9 Estra-1,3,5(10)-triene-3,15,16,17-tetrol 11 Miroestrol
10 Holaromine

O
O
O
O OH
OH RO 12 Jaborosalactone 7
OH O
O H
HO O

O
O H OH
HO HO
16
H
HO 14 Meteogenin, R = H
13 Gu-2-O- -D-Andirobicin B
15 Meteogenin Ac, R = Ac O
O H
H
HO
O

O
O O
HO O
OH
OH OH

OH O OH
HO O

18 Luvigenin
H O
HO HO

OH HO 19 Cayaponoside A4
17 Jaborosalactone 45

O
O

O 22
H H
HO
HO

Me H
HO O
HO
O
NaO3SO

20 Xuxuasin B 21 6-Oxotingenol 23 Equilin Sulfate

OH

O HO
24
OH

Fig. 1 Ring A monoaromatic plant steroids

4666
et al. 2012). The extract of bark from the main wooden rod of
ketapang Terminalia catappa (Combretaceae) contained es-
trone (1), estriol (3), equilin (4), equilin sulfate (23), and a
steroid (24) (Su et al. 2013). The ethanol extract of leaves of
Terminalia catappa shows an antimicrobial activity against
Escherichia coli, Staphylococcus aureus, and Candida
albicans, as well as antifungal activity against
Epidermophyton floccosum and C. albicans (Sukandar et al.
2004, 2006, 2007). Predicted biological activity for
monoaromatic steroids isolated from plants is shown in
Table 1.
Distribution of A, B, C, and D rings
monoaromatic steroids in nature
The ring A-aromatic bile acid, 18 3-hydroxy-19-norchola-
1,3,5(10),22-tetraen-24-oic acid (25 structure in Fig. 2), was
isolated from the sponge Sollasella moretonensis, collected
from the seabed of northern Queensland (Lu et al. 2010). A
4-hydroxy-6-oxopregnane-3-glycoside (26) with an aromatic
ring A was isolated from a Pohnpei sponge, Cribrochalina
olemda (Yeung et al. 1994). Both steroids have not been stud-
ied for their biological activity. Geodisterol-3-O-sulfite (27)
was isolated from marine sponge Topsentia sp. and shown
antifungal activity against Candida albicans (Di Girolamo
et al. 2009).
24,26-Cyclo-19-norcholesta-1,3,5(10),22-tetraen-3-ol (28)
was isolated from the Hainan soft coral Dendronephthya
studeri (Yan et al. 2011). Unusual steroid thioester,
parathiosteroids C (29), was isolated from the 2-propanol ex-
tract of the soft coral Paragorgia sp. collected in Madagascar.
This compound displayed cytotoxicity against a panel of three
human tumor cell lines at the micromolar levels (Poza et al.
2008).
Monoaromatic B ring steroids are rare natural lipids
and are found predominantly in the mushroom kingdom
and are also present in marine sediments or oils. Thus,
phycomysterols A (29) and C (30) which possess a new
natural 19-norergostane skeleton with an aromatic B ring
are synthesized a filamentous fungus Phycomyces
blakesleeanus, and phycomysterol A showed anti-HIV ac-
tivity (Barrero et al. 1998). Gibberella zeae (syn.
Fusarium roseum) is a worldwide pathogenic fungus that
can produce a wide variety of steroids, as well as
(22E,24R)-1(10→6)-abeoergosta-5,7,9,22-tetraen-3α-ol
(31) (Liu et al. 2011). This compound showed significant
cytotoxicity toward murine colorectal CT26 and human
leukemia K562 cancer cell lines. Steroidal hydrocarbons
(33, 39, and 43) were detected in sediments and petro-
leum (Brassell et al. 1983; MacKenzie et al. 1982). An
aromatic B ring called topsentisterol E1 (34) was isolated
from bioactive fractions of a marine sponge Topsentia sp.
Appl Microbiol Biotechnol (2018) 102:4663–4674
(Luo et al. 2006). The presence of this unusual steroid
may indicate that it is synthesized by the endophytic fun-
gus which is a symbiont in this kind of sponge. A struc-
turally unique C25 steroid named phomarol was isolated
from a cultured fungus, Phoma sp. derived from the giant
jellyfish Nemopilema nomurai. Phomarol is unique with a
7-membered carbocyclic A ring [1(10→19)abeo], an aro-
matic B ring, and a side chain cyclized to form a fused
pentacyclic skeleton (Kim et al. 2016).
An interesting lanostanoid, 19-nor-lanosta-5(10),6,8,24-
tetraene-1α,3β,12β,22S-tetraol (36), was isolated from an en-
dophytic fungus, Diaporthe sp. LG23, inhabiting leaves of the
Chinese medicinal plant Mahonia fortunei. This compound,
an unusual fungus-derived 19-nor-lanostane tetracyclic
triterpenoid with an aromatic B ring system, exhibited pro-
nounced antibacterial efficacy against both Gram-positive
and Gram-negative bacteria, especially the clinical isolates
of Streptococcus pyogenes and Pseudomonas aeruginosa as
well as a human pathogenic strain of Staphylococcus aureus
(Li et al. 2015).
Monoaromatic C-ring steroids are a rare group of natural
lipids, mainly found in vegetable oils, as well as in marine
sediments and oils. The C20 C-ring monoaromatic hydroxy
steroid acids (37 and 38) were found in the Alberta oil sands,
which apparently can also be synthesized by soil fungi
(Rowland et al. 2011).
A Korean marine sponge, Phorbas sp. yielded unusual
unprecedented sesterterpenoid phorone A with an aromatic
D ring (40), but without studying the biological activity
(Wang et al. 2012).
Unique nakiterpiosinone (41) is related C-nor-D-
homosteroid isolated from the sponge Terpios hoshinota that
has shown promise as anticancer agent (Gao et al. 2010).
Akaol A (42), a marine sesquiterpene quinol, was found in a
marine sponge of the genus Aka collected from Yap Island,
Micronesia (Venugopal et al. 2003).
Two minor steroids with an aromatic E ring (44 and 45)
were isolated minor components from the extract of
Salpichroa origanifolia plants harvested in the provinces of
Buenos Aires and Cordoba in Argentina (Misico et al. 2011).
Terpene-ketide, haliclotriol A (46), has been isolated from the
Indonesian sponge Haliclona sp. (Crews and Harrison 2000).
Halicloic acid B (47) has been isolated from the marine
sponge Haliclona (syn Halichoclona) sp. collected in the
Philippines. This steroid has the new rearranged Bhaliclane^
meroterpenoid carbon skeleton, and they showed inhibitory
activity against an indoleamine 2,3-dioxygenase (Williams
et al. 2012). Steroidal hydrocarbons (48 and 49) were isolated
from marine sediments and petroleum (Falk and Wolkenstein
2017; Oliveira et al. 2012; Jacob et al. 2007). Predicted bio-
logical activity for monoaromatic steroids isolated from
plants, fungi, invertebrates, marine sediments, and oils is
shown in Table 2.
Appl Microbiol Biotechnol (2018) 102:4663–4674 4667

Table 1 Biological activities of ring A monoaromatic steroids (1–24)

No. Predicted biological activities of monoaromatic steroids (Pa)*

1 Antiseborrheic (0.964); ovulation inhibitor (0.942); alopecia treatment (0.927); cardiovascular analeptic (0.924)
Antihypercholesterolemic (0.871); neuroprotector (0.863); vasoprotector (0.794); antipruritic (0.742)
Prostate disorders treatment (0.737); lipid metabolism regulator (0.730); anesthetic general (0.725); diuretic (0.685)
2 Antiseborrheic (0.973); alopecia treatment (0.967); antihypercholesterolemic (0.894); ovulation inhibitor (0.889)
Neuroprotector (0.870); anesthetic general (0.868); respiratory analeptic (0.851); vasoprotector (0.811); acute neurologic
disorders treatment (0.793); prostate disorders treatment (0.729); antipruritic (0.720); anti-inflammatory (0.713)
3 Antiseborrheic (0.963); alopecia treatment (0.940); anesthetic general (0.845); ovulation inhibitor (0.832)
Respiratory analeptic (0.823); acute neurologic disorders treatment (0.822); neuroprotector (0.815); antihypercholesterolemic (0.791);
antieczematic (0.753); antipruritic (0.745); vasoprotector (0.721); prostate disorders treatment (0.717)
4 Antiseborrheic (0.904); antihypercholesterolemic (0.856); ovulation inhibitor (0.847); cardiovascular analeptic (0.842)
Alopecia treatment (0.807); lipid metabolism regulator (0.788); apoptosis agonist (0.750); prostate disorders treatment (0.725)
5 Antiseborrheic (0.928); alopecia treatment (0.907); antihypercholesterolemic (0.885); apoptosis agonist (0.801); hepatic
disorders treatment (0.739); ovulation inhibitor (0.726); prostate disorders treatment (0.717); vasoprotector (0.716)
6 Antiseborrheic (0.933); alopecia treatment (0.915); acute neurologic disorders treatment (0.871); respiratory analeptic (0.843)
Vasoprotector (0.811); neuroprotector (0.785); anesthetic general (0.753); ovulation inhibitor (0.740); antieczematic (0.728)
Antipruritic (0.718); apoptosis agonist (0.710); anti-inflammatory (0.706); antihypercholesterolemic (0.690)
7 Antiseborrheic (0.910); cardiovascular analeptic (0.882); ovulation inhibitor (0.860); respiratory analeptic (0.846)
Acute neurologic disorders treatment (0.844); alopecia treatment (0.821); vasoprotector (0.794); neuroprotector (0.778)
8 Antiseborrheic (0.945); respiratory analeptic (0.879); alopecia treatment (0.873); ovulation inhibitor (0.765)
Neuroprotector (0.762); cardiovascular analeptic (0.692); immunosuppressant (0.673); apoptosis agonist (0.657)
9 Antiseborrheic (0.953); alopecia treatment (0.924); acute neurologic disorders treatment (0.849); vasoprotector (0.795)
Anti-inflammatory (0.788); ovulation inhibitor (0.778); respiratory analeptic (0.760); neuroprotector (0.734)
10 Psychotropic (0.815); attention deficit/hyperactivity disorder treatment (0.744); sleep disorders treatment (0.701)
Antiobesity (0.649); antipsychotic (0.641); anesthetic (0.595); ovulation inhibitor (0.586); antineoplastic (0.580)
11 Postmenopausal disorders treatment (0.945); anti-inflammatory (0.669); antiobesity (0.567)
12 Antieczematic (0.917); lipid metabolism regulator (0.913); cytostatic (0.891); antineoplastic (0.876); hepatoprotectant (0.845)
Immunosuppressant (0.792); apoptosis agonist (0.784); respiratory analeptic (0.784); antiseborrheic (0.780)
Anti-inflammatory (0.770); antihypercholesterolemic (0.767); antifungal (0.753); antipruritic (0.728)
13 Hepatoprotectant (0.928); chemopreventive (0.919); proliferative diseases treatment (0.914); neuroprotector (0.860)
Antineoplastic (0.837); vasoprotector (0.824); anti-inflammatory (0.808); antipruritic (0.780); immunosuppressant (0.775)
Anticarcinogenic (0.769); antifungal (0.768); antidiabetic (0.732); apoptosis agonist (0.719); antihypercholesterolemic (0.718)
14 Apoptosis agonist (0.893); anti-inflammatory (0.873); hypolipemic (0.854); antineoplastic (0.827); proliferative diseases
treatment (0.743); antifungal (0.709); anticarcinogenic (0.704); lipoprotein disorders treatment (0.695); antipruritic (0.694)
15 Apoptosis agonist (0.883); hypolipemic (0.863); anti-inflammatory (0.855); antineoplastic (0.826); proliferative diseases
treatment (0.767); antifungal (0.735); immunosuppressant (0.701); lipoprotein disorders treatment (0.671)
16 Antieczematic (0.912); antineoplastic (0.879); hepatoprotectant (0.775); apoptosis agonist (0.775); immunosuppressant (0.744)
Antifungal (0.731); anti-inflammatory (0.715); antiparasitic (0.667); antipruritic (0.637); antipsoriatic (0.610)
17 Antieczematic (0.845); antineoplastic (0.782); genital warts treatment (0.736); anti-inflammatory (0.662)
18 Apoptosis agonist (0.896); hypolipemic (0.850); antineoplastic (0.843); anti-inflammatory (0.814); proliferative diseases
treatment (0.713); atherosclerosis treatment (0.685); Alzheimer’s disease treatment (0.675); antifungal (0.645)
19 Chemopreventive (0.887); hepatoprotectant (0.880); anti-inflammatory (0.819); antineoplastic (0.794); proliferative diseases
treatment (0.784); antipruritic (0.773); antifungal (0.772); acute neurologic disorders treatment (0.770); antidiabetic (0.769)
Antihypercholesterolemic (0.734); immunosuppressant (0.730); antibacterial (0.727); spasmolytic (0.719)
20 Antineoplastic (0.909); anti-inflammatory (0.822); apoptosis agonist (0.790); hepatoprotectant (0.747)
Immunosuppressant (0.727); antileukemic (0.618); prostate disorders treatment (0.608); antifungal (0.587)
21 Antineoplastic (0.888); apoptosis agonist (0.847); antieczematic (0.847); anti-inflammatory (0.830); immunosuppressant
(0.739); antiischemic, cerebral (0.717); antipruritic (0.695); hepatoprotectant (0.658); ovulation inhibitor (0.644)
22 Antineoplastic (0.802); apoptosis agonist (0.789); anti-inflammatory (0.786); antiseborrheic (0.754); antieczematic (0.720)
Prostate disorders treatment (0.685); antiosteoporotic (0.683); antipsoriatic (0.627); atherosclerosis treatment (0.611)
23 Acute neurologic disorders treatment (0.867); diuretic (0.813); antineoplastic (0.812); alopecia treatment (0.792)
Male reproductive dysfunction treatment (0.759); antiosteoporotic (0.716); prostate disorders treatment (0.662)
24 Antihypercholesterolemic (0.959); antiseborrheic (0.873); respiratory analeptic (0.848); antineoplastic (0.832)
Hypolipemic (0.808); antipruritic (0.791); antiosteoporotic (0.777); antieczematic (0.775); immunosuppressant (0.753)
Hepatoprotectant (0.729); anti-inflammatory (0.728); anesthetic general (0.706); chemopreventive (0.661)

*Only activities with Pa > 0.7 are shown. The main biological activity has a value where Pa is more than 0.7, but for some steroids, values in which Pa are
more than 0.5 are indicated

Distribution of di- and triaromatic steroids
in nature
Diaromatic and triaromatic steroids (50–80 structures in
Figs. 2 and 3) are rare groups of natural lipids, and these
compounds have been isolated and identified in marine sedi-
ments, oils, and sedimentary rocks (Falk and Wolkenstein
2017; Rowland et al. 2011; Nakanishi 1974). Diaromatic or
naphthalene-containing steroids are produced mainly by fungi
(Zuhrotun et al. 2010).
4668 Appl Microbiol Biotechnol (2018) 102:4663–4674

OH
OH

AcO H
H O
H OH

A H H HO O
H H
HO OH OH O
25 NaO3SO
26 Hapaioside O 27
H
N
S
H
H
O

H 29 Parathiosteroid C B H
H H
HO
HO H H
30 Phycomysterol A
28
HO

HO

H B B
32 33 B H
HO
34

31 Phycomysterol C
HO
OH COOMe
HO
OH

O C
OH

H
COOH 38
HO OH
C

OH
B OH 37
B H
O
HO
HO 35 Phomarol
36 OH Cl O
NaO3SO
OH
Cl
O

H OH
D D
O OH
C H D
H OH

39 H
OH O
H H 42 Akaol A
H

40 Phorone A HO

O Br
O OH
D 41 Nakiterpiosinone O
O
D
O OH
O HO
D 45 Salpichrolide J
43
OH
O OH
44 Salpichrolide C
OH
HOOC E
OH HO
OH
E
E
OH

COOH H 48
H
HO
HO E
HO H H H
47 Halicloic acid B
O
H 46 Haliclotriol A

49

Fig. 2 Monoaromatic A, B, C, D, and E rings derived from fungi, invertebrates, plants, sediments, and oils
Appl Microbiol Biotechnol (2018) 102:4663–4674 4669

Table 2 Biological activities of monoaromatic steroids (25–49)

No. Predicted biological activities of monoaromatic steroids (Pa)*

25 Antihypercholesterolemic (0.961); antiseborrheic (0.934); antieczematic (0.863); antiosteoporotic (0.854)

Anesthetic general (0.851); antineoplastic (0.840); alopecia treatment (0.835); antipsoriatic (0.807); apoptosis agonist (0.787)
Antipruritic (0.774); anti-inflammatory (0.760); immunosuppressant (0.729); prostate disorders treatment (0.724)
Proliferative diseases treatment (0.711); hypolipemic (0.711); respiratory analeptic (0.693); contraceptive (0.689)
26 Neuroprotector (0.979); respiratory analeptic (0.970); antihypercholesterolemic (0.953); antiinfective (0.933)
Antiprotozoal (Leishmania) (0.922); hepatoprotectant (0.898); antineoplastic (0.888); vasoprotector (0.814)
Hemostatic (0.794); antifungal (0.786); anti-inflammatory (0.786); immunosuppressant (0.785); antimycobacterial (0.777)
27 Antihypercholesterolemic (0.860); antineoplastic (0.805); anti-inflammatory (0.754); chemopreventive (0.721)
Immunosuppressant (0.720); apoptosis agonist (0.720); hypolipemic (0.712); hepatoprotectant (0.709); antifungal (0.670)
28 Antihypercholesterolemic (0.907); antiseborrheic (0.890); antieczematic (0.843); antineoplastic (0.836)
Antiosteoporotic (0.829); apoptosis agonist (0.788); anti-inflammatory (0.765); antipruritic (0.764); antipsoriatic (0.760)
Respiratory analeptic (0.720); immunosuppressant (0.705); prostate disorders treatment (0.701)
29 Antiseborrheic (0.790); antihypercholesterolemic (0.764); anti-inflammatory (0.695); radioprotector (0.664)
30 Antihypercholesterolemic (0.929); respiratory analeptic (0.885); antieczematic (0.863); hypolipemic (0.797)
Immunosuppressant (0.790); antineoplastic (0.786); antiosteoporotic (0.768); antifungal (0.751); antipruritic (0.744)
Anesthetic general (0.737); chemopreventive (0.726); apoptosis agonist (0.722); anti-inflammatory (0.702)
31 Antihypercholesterolemic (0.935); antieczematic (0.895); respiratory analeptic (0.862); apoptosis agonist (0.850)
Antineoplastic (0.840); antiosteoporotic (0.822); antipsoriatic (0.811); immunosuppressant (0.792); antipruritic (0.790)
Anti-inflammatory (0.783); antiparkinsonian, rigidity relieving (0.773); proliferative diseases treatment (0.753)
32 Antihypercholesterolemic (0.950); apoptosis agonist (0.898); antineoplastic (0.880); antiparkinsonian, rigidity relieving (0.875)
Antieczematic (0.851); antiosteoporotic (0.837); antipsoriatic (0.822); immunosuppressant (0.794); antipruritic (0.717)
33 Antieczematic (0.843); antihypercholesterolemic (0.806); antiosteoporotic (0.773); antipruritic (0.739); antineoplastic (0.729)
Respiratory analeptic (0.710); antipsoriatic (0.707); immunosuppressant (0.704); apoptosis agonist (0.682)
34 Antihypercholesterolemic (0.914); apoptosis agonist (0.894); antineoplastic (0.879); hypolipemic (0.858); antieczematic (0.819)
Antiosteoporotic (0.817); antipsoriatic (0.806); immunosuppressant (0.791); anti-inflammatory (0.719); contraceptive (0.681)
35 Antineoplastic (0.922); immunosuppressant (0.774); antifungal (0.764); anti-inflammatory (0.757); antiosteoporotic (0.704)
36 Antineoplastic (0.899); apoptosis agonist (0.896); anti-inflammatory (0.795); antieczematic (0.781); antipsoriatic (0.754)
Immunosuppressant (0.746); antifungal (0.678); hepatoprotectant (0.646); antihypercholesterolemic (0.597)
37 Neuroprotector (0.942); antiallergic (0.830); anti-inflammatory (0.820); antiasthmatic (0.811); antiseborrheic (0.795)
Antieczematic (0.791); alopecia treatment (0.750); antineoplastic (0.739); antipruritic (0.736); antihypercholesterolemic (0.735)
38 Antieczematic (0.831); neuroprotector (0.829); antiallergic (0.731); anti-inflammatory (0.728); antiseborrheic (0.716)
Immunosuppressant (0.708); antineoplastic (0.702); antihypercholesterolemic (0.697); hypolipemic (0.670)
39 Anticonvulsant (0.877); antipruritic (0.728); neuroprotector (0.674); antineoplastic (0.671); hypolipemic (0.656)
40 Apoptosis agonist (0.828); anti-inflammatory (0.813); antineoplastic (0.798); cytoprotectant (0.727); neuroprotector (0.715)
Hepatoprotectant (0.712); immunosuppressant (0.683); vasodilator, peripheral (0.669); antipsoriatic (0.643)
41 Antineoplastic (0.782); antibacterial (0.736); apoptosis agonist (0.734); antifungal (0.695); immunosuppressant (0.647)
42 Acute neurologic disorders treatment (0.867); antineoplastic (0.797); hepatoprotectant (0.776); anti-inflammatory (0.771)
Chemopreventive (0.748); antiulcerative (0.715); antiosteoporotic (0.632); diuretic (0.623); antifungal (0.621)
43 Anti-inflammatory (0.825); apoptosis agonist (0.793); antieczematic (0.748); antineoplastic (0.747); antipruritic (0.714)
44 Antineoplastic (0.884); apoptosis agonist (0.848); immunosuppressant (0.700); antiallergic (0.692); antimitotic (0.617)
45 Antineoplastic (0.799); antiprotozoal (plasmodium) (0.776); apoptosis agonist (0.716); immunosuppressant (0.667)
46 Antineoplastic (0.858); antihypercholesterolemic (0.839); cell adhesion molecule inhibitor (0.795); thrombolytic (0.783)
Immunosuppressant (0.781); hypolipemic (0.765); antibacterial (0.688); apoptosis agonist (0.687); chemopreventive (0.673)
47 Antineoplastic (0.841); immunosuppressant (0.722); anti-inflammatory (0.675); apoptosis agonist (0.669)
48 Antineoplastic (0.844); apoptosis agonist (0.792); anti-inflammatory (0.780); antipsoriatic (0.667); hypolipemic (0.661)
49 Antieczematic (0.771); acute neurologic disorders treatment (0.768); anti-inflammatory (0.757); antineoplastic (0.724)
Apoptosis agonist (0.706); hypolipemic (0.597); immunosuppressant (0.592); prostate disorders treatment (0.561)

*Only activities with Pa > 0.7 are shown. The main biological activity has a value where Pa is more than 0.7, but for some steroids, values in which Pa are
more than 0.5 are indicated

6,8-Didehydroestrone (50), as well as estra-1,3,5 (10), 6,8-
pentaen-3-ol-17-one, a steroidal hormone called equilenin,
was first isolated from the urine of pregnant mares in 1936
by Desmond Beall (1936). Later, in 1938, equilenin sulfate
(51) was also isolated from the urine of pregnant mares by
Schachter and Marrian (1938), and in 1939, it was synthesized
by Bachmann et al. (1939) 17α-Dihydroequilenin (52) and
estra-1,3,5,7,9-pentaen-17-one (53) derivatives of equilenin
were also excreted from horses’ urine (Fritz and Speroff
2012).
Three naphthalene-containing steroids (53–56) have been
found in ketapang bark (Terminalia catappa), but the authors
believe that these mothballs produce naphthalenic steroids
(Zuhrotun et al. 2010). It is known that Terminalia catappa
and Terminalia mantaly (Combretaceae) are medicinal plants
used in Cameroon to treat several diseases. As studies of these
plants have shown, they contain endophytic fungi (Toghueo
et al. 2017a). Interesting strains of endophytic fungi isolated
from these plants are of great variety. Thus, Pestalotiopsis
spp., Penicillium sp., Penicillium chermesinum, Xylaria sp.,
4670 Appl Microbiol Biotechnol (2018) 102:4663–4674

O O OH O

A B H H H H

HO NaO3SO HO
50 Equilenin 51 Equilenin sulphate 52 17 -Dihydroequilenin 53 Estra-1,3,5,7,9-pentaen-17-one

OH
O OH

O
HO
H
H H

HO OH
HO HO
54 OH 55 OH 56 OSO3Na 57

H
H

60 61
59
58

61 62 64
63

C OH
HO

A B

66 Cinanthrenol A 67 68 69

73
72
70 71

74
76
75

HO
C D

A B
80
77
78 79

Fig. 3 Di- and triaromatic steroids and terpenoids derived from fungi, invertebrates, sediments, and petroleum
Appl Microbiol Biotechnol (2018) 102:4663–4674 4671

Table 3 Biological activities of di- and triaromatic steroids (50–80)

Predicted biological activities of di- and triaromatic steroids (Pa)*

No.

50 Antiseborrheic (0.925); ovulation inhibitor (0.866); alopecia treatment (0.856); antineoplastic (0.824); neuroprotector (0.798)
Acute neurologic disorders treatment (0.784); analeptic (0.777); vasoprotector (0.776); lipid metabolism regulator (0.768)
Male reproductive dysfunction treatment (0.765); menopausal disorders treatment (0.750); antihypercholesterolemic (0.746)
Antipruritic (0.720); antiosteoporotic (0.716); contraceptive (0.677); prostate disorders treatment (0.663)
51 Acute neurologic disorders treatment (0.925); alopecia treatment (0.844); diuretic (0.824); male reproductive dysfunction treatment (0.791); antineoplastic
(0.790); laxative (0.764); anti-inflammatory (0.695); antiosteoporotic (0.683)
52 Antiseborrheic (0.944); alopecia treatment (0.933); acute neurologic disorders treatment (0.826); antineoplastic (0.818)
Respiratory analeptic (0.811); neuroprotector (0.807); vasoprotector (0.795); antihypercholesterolemic (0.791)
Antiosteoporotic (0.779); menopausal disorders treatment (0.775); antieczematic (0.747); ovulation inhibitor (0.746)
53 Antiseborrheic (0.875); ovulation inhibitor (0.846); antineoplastic (0.821); male reproductive dysfunction treatment (0.815)
Alopecia treatment (0.807); vasoprotector (0.761); neuroprotector (0.747); analeptic (0.715); antieczematic (0.697)
54 Antiseborrheic (0.942); alopecia treatment (0.907); neuroprotector (0.837); antineoplastic (0.833); vasoprotector (0.831)
Acute neurologic disorders treatment (0.828); respiratory analeptic (0.821); antihypercholesterolemic (0.789)
Antiosteoporotic (0.769); menopausal disorders treatment (0.732); ovulation inhibitor (0.722); apoptosis agonist (0.715)
Antieczematic (0.709); anti-inflammatory (0.707); antipruritic (0.687); contraceptive (0.674)
55 Antiseborrheic (0.922); ovulation inhibitor (0.843); antineoplastic (0.839); neuroprotector (0.829); vasoprotector (0.817)
Alopecia treatment (0.807); acute neurologic disorders treatment (0.786); analeptic (0.778); antihypercholesterolemic (0.743)
Lipid metabolism regulator (0.723); antipruritic (0.719); menopausal disorders treatment (0.708); antiosteoporotic (0.703)
56 Acute neurologic disorders treatment (0.932); alopecia treatment (0.928); hemostatic (0.851); laxative (0.833)
Antiseborrheic (0.825); antineoplastic (0.810); diuretic (0.751); antiosteoporotic (0.734); anti-inflammatory (0.719)
57 Apoptosis agonist (0.924); antineoplastic (0.868); antiseborrheic (0.847); antioxidant (0.776); neuroprotector (0.728)
58 Antieczematic (0.849); antiosteoporotic (0.837); antiseborrheic (0.830); antineoplastic (0.735); antipruritic (0.696)
59 Antieczematic (0.881); antihypercholesterolemic (0.860); respiratory analeptic (0.847); anesthetic general (0.816)
Antipruritic (0.795); antiosteoporotic (0.776); antineoplastic (0.732); immunosuppressant (0.720); antipsoriatic (0.703)
60 Apoptosis agonist (0.758); anti-inflammatory (0.744); antineoplastic (0.733); antiseborrheic (0.701)
Lipid metabolism regulator (0.664); antieczematic (0.649); acute neurologic disorders treatment (0.629)
61 Apoptosis agonist (0.758); anti-inflammatory (0.744); antineoplastic (0.733); antiseborrheic (0.701)
62 Anti-inflammatory (0.807); antieczematic (0.801); apoptosis agonist (0.746); antineoplastic (0.726); antipruritic (0.699)
63 Antiinfertility, female (0.796); anti-inflammatory (0.794); antineoplastic (0.756); antieczematic (0.750); antipruritic (0.680)
64 Antineoplastic (0.697); ovulation inhibitor (0.683); antiosteoporotic (0.668); antieczematic (0.665); contraceptive (0.613)
65 Antiseborrheic (0.824); prostate disorders treatment (0.699); antieczematic (0.669); anti-inflammatory (0.661)
66 Antiseborrheic (0.827); antineoplastic (0.825); Alzheimer’s disease treatment (0.824)
Neurodegenerative diseases treatment (0.809); psychotropic (0.700); alopecia treatment (0.683)
67 Antieczematic (0.767); antidyskinetic (0.670); anti-inflammatory (0.665); antineurotic (0.665); antiseborrheic (0.625)
68 Antieczematic (0.695); anti-inflammatory (0.689); autoimmune disorders treatment (0.652); antineurotic (0.632)
69 Antieczematic (0.767); antidyskinetic (0.670); anti-inflammatory (0.665); antineurotic (0.665); antiseborrheic (0.625)
70 Antieczematic (0.782); antineurotic (0.709); antipruritic (0.641); antiseborrheic (0.620); antipsoriatic (0.619)
71 Neuroprotector (0.685); antiseborrheic (0.651); acute neurologic disorders treatment (0.647); anti-inflammatory (0.595)
72 Hypolipemic (0.724); anticonvulsant (0.649); antieczematic (0.641); anti-inflammatory (0.632); antipruritic (0.621)
73 Antieczematic (0.885); antipsoriatic (0.757); anti-inflammatory (0.735); antipruritic (0.707); neuroprotector (0.680)
74 Antipruritic (0.736); phobic disorders treatment (0.734); antieczematic (0.709); anticonvulsant (0.661); antipsoriatic (0.632)
75 Antieczematic (0.691); antipsoriatic (0.622); psychotropic (0.611); anticonvulsant (0.570); antipruritic (0.560)
76 Apoptosis agonist (0.758); anti-inflammatory (0.744); antineoplastic (0.733); antiseborrheic (0.701)
77 Antiseborrheic (0.844); acute neurologic disorders treatment (0.778); neuroprotector (0.733); antineoplastic (0.709)
Alopecia treatment (0.697); anti-inflammatory (0.650); menopausal disorders treatment (0.628); cytoprotectant (0.627)
78 Anti-inflammatory (0.782); antieczematic (0.771); antineoplastic (0.738); antiseborrheic (0.672); apoptosis agonist (0.669)
79 Anti-inflammatory (0.808); antiseborrheic (0.777); antineoplastic (0.709); antieczematic (0.704); apoptosis agonist (0.675)
Ovulation inhibitor (0.608); prostate disorders treatment (0.586); alopecia treatment (0.572)
80 Phobic disorders treatment (0.775); antiseborrheic (0.711); kidney function stimulant (0.703); fibrinolytic (0.626)

*Only activities with Pa > 0.7 are shown. The main biological activity has a value where Pa is more than 0.7, but for some steroids, values in which Pa are
more than 0.5 are indicated

Paraconiothyrium variabile, Penicillium sp. were isolated
from Terminalia catappa, and Xylaria spp., Lasiodiplodia
theobromae, Cercospora spp., Cercospora olivascens,
Phoma microchlamidospora, Fusarium sp., Diaporthe sp.,
Phomopsis sp., and Colletotrichum gloeosporioides were iso-
lated from Terminalia mantaly (Toghueo et al. 2017b).
New diaromatic steroid (57) which contains an uncommon
naphthyl A/B ring system similar to equilenin was isolated
from a Hawaiian sponge of the genus Strongylophora, which
was collected off the southern coast of Lanai (Parrish et al.
2016). Diaromatic steroid, (17β,20R,22E,24R)-19-
norergosta-1,3,5,7,9,14,22-heptaene (59) was isolated from
the ascomycete Daldinia concentrica (Qin and Liu 2004).
Astonishing diversity naphthalenic steroid hydrocarbons
(58–65) were found in marine sediments, fossil plants and
algae, ancient petrified rocks, and petroleum (Breger 1966;
4672
Brassell et al. 1983; Rowland et al. 2011; Huang et al. 2016;
Cheng et al. 2017).
Triaromatic steroids are de facto phenanthrene-containing
steroids (66–70) which in nature are found only a few pieces.
Thus, cinanthrenol A (66), a new steroid composed of a phen-
anthrene and a spiro[2,4]heptane system, was isolated from
the marine sponge Cinachyrella sp. It is the first
phenanthrene-containing steroid with estrogen activity
(Machida et al. 2014). Cinanthrenol A (66) was demonstrated
cytotoxic activity against P-388 and HeLa cells, and as an
estrogen receptor inhibitor.
Astonishing diversity triaromatic and/or polyaromatic ste-
roid hydrocarbons (67–80 structures in Fig. 3) were found in
fossil plants and algae, marine sediments, and petroleum
(Ludwig et al. 1981; Brassell et al. 1983; Mackenzie et al.
1982; Rowland et al. 2011).
Oleanane-related triterpenoid (77) bearing a unique C-2
oxygenated functionality has been identified as the predomi-
nant triterpenoids from a 4900-year-old oak wood sample
buried in freshwater sediment (Schnell et al. 2012; Le
Milbeau et al. 2010).
Three phenanthrenic steroids (76, 78, and 79) along with
stigmast-4-ene, stigmast-5-ene, stigmastanol, stigmastanol-3-
one, 24-ethylcholesta-4,6,22-triene, and β-sitosterol were
identified from the fossil cones of Taxodium balticum with
stigmastanol-3-one in T. dubium (Su et al. 2013). Predicted
biological activity for monoaromatic steroids isolated from
fungi, invertebrates, marine sediments, and petroleum is
shown in Table 3.
Conclusion
In a relatively small survey, we have demonstrated the distri-
bution of mono-, di- and triaromatic steroids in various eco-
logical niches, terrestrial, aquatic, and geological. We demon-
strated that aromatic steroids exhibit a wide range of biologi-
cal activities, but mostly they likely possess anticancer, anti-
inflammatory, neuroprotection, and other activities. The infor-
mation obtained will be of interest to biologists, chemists, and
pharmacologists, as well as to the pharmaceutical industry.
Acknowledgements The work was performed in the framework of the
Program for Basic Research of State Academies of Sciences for 2013–
2020.
Compliance with ethical standards
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Conflict of interest The authors declare that they have no competing
interests.
Appl Microbiol Biotechnol (2018) 102:4663–4674
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