Naturally occurring aromatic steroids and their ...

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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 Aromatic steroids are lipids that contain at least one or more aromatic ring(s) in a steroid skeleton. Aromatic steroids 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 samples 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 [email protected] 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

in marine sediments and oil, and less in geological samples (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 organisms, although much more is found in geological samples, in marine sediments, or in oil. For triaromatic steroid hydrocarbons, 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 aromatic steroids, which are found in living organisms, is poorly studied, and the same compounds found in geological and marine sediments have not been studied. We selected 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 relationship between structure and activity, and this principle is called SAR (structure-activity relationship). We used the computer program PASS, containing about one million chemical compounds and more than 8000 biological activities, and estimated 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

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than one million drugs, drug candidates, and lead compounds. The algorithm of PASS and its practical utilization are described 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 discovered in 1920s from the urine of pregnant women, independently 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)-triene-3-ol-17-one (1), also known as estrone, is a naturally occurring estrane steroid, which is produced in vivo from androstenedione and/or testosterone via estradiol. The abovementioned estrogens show estrogenic activity with various 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) estrogens 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 hormones and their physiological role in plants. These hormones, such as 17β-estradiol, androsterone, testosterone, or progesterone, 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 dihydrotestosterone) in 70% of species, and estrogens (estrone and 17β-

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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 containing 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-methyl19-nor-25D-spirosta-1,3,5(10)-trien-11α-ol (14) and its acetate (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 compound 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 steroid 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

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4665 OH

O

H

H

A

OH

H

OH

H

H

H

H

H

HO

HO

O

H

H

HO

2 Estradiol

1 Estrone

3 Estriol

OH

OH

H

HO

4 Equilin

O

O H

H

H

H

H HO

HO

N

OH

H

HO

7 Hippulin

6 8,9-Dehydroestradiol

5 17 -Dihydroequilin

H

HO

8 16,17-Epoxyestra-1,3,5(10)-trien-3-ol

H

OH H OH

H H

OH H

H

H

O

OH

H

H

O

HO

HO

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

OH

OH

O

11 Miroestrol

10 Holaromine O

O

O

O

OH

OH

RO

HO

12 Jaborosalactone 7

OH

O

O

H

O

O O HO

OH

H HO

HO

16 H

14 Meteogenin, R = H 15 Meteogenin Ac, R = Ac

13 Gu-2-O- -D-Andirobicin B O

O

O

H H

HO

O O HO

O

O

OH

OH

OH O

OH

H

HO

OH

O

18 Luvigenin

O HO

HO

HO

OH

19 Cayaponoside A4

17 Jaborosalactone 45

O

22

O

H

H

HO

O

HO Me O

HO

HO

O NaO3SO

20 Xuxuasin B

21 6-Oxotingenol

23 Equilin Sulfate OH

H O OH

Fig. 1 Ring A monoaromatic plant steroids

HO

24

H

O

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et al. 2012). The extract of bark from the main wooden rod of ketapang Terminalia catappa (Combretaceae) contained estrone (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-norchola1,3,5(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 studied 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 extract 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 activity (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 petroleum (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.

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(Luo et al. 2006). The presence of this unusual steroid may indicate that it is synthesized by the endophytic fungus which is a symbiont in this kind of sponge. A structurally 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 aromatic 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),6,8,24tetraene-1α,3β,12β,22S-tetraol (36), was isolated from an endophytic 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 pronounced 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-Dhomosteroid 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 biological 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 Table 1

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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) 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) 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) 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) 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) 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) 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) 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) 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) 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) Postmenopausal disorders treatment (0.945); anti-inflammatory (0.669); antiobesity (0.567) 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) 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) 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) 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) 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) Antieczematic (0.845); antineoplastic (0.782); genital warts treatment (0.736); anti-inflammatory (0.662) 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) 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) 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) 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) 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) 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) 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)

2

3

4 5 6

7 8 9 10 11 12

13

14 15 16 17 18 19

20 21 22 23 24

*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 sediments, 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).

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Appl Microbiol Biotechnol (2018) 102:4663–4674 O OH OH

A

H

AcO

H

O

H

H

H

HO

O

HO

H OH

OH

25

H

O NaO3SO

26 Hapaioside

OH

27

O H N S

H H

O

H

B

29 Parathiosteroid C

H H

H

HO H

HO

28

H

30 Phycomysterol A

HO

HO

B

H

B

32

B

33

HO

H

34

31 Phycomysterol C HO

OH

OH O

COOMe

HO

C

OH H

COOH

OH

HO

B

38

C

OH

B

OH

37

H

O

HO HO

35 Phomarol

36

Cl

OH

O

NaO3SO

Cl

OH

O H

C

OH

D

O

D

OH

D

H

OH

H

39

H

H

O

OH

40 Phorone A

H

O

D

Br

41 Nakiterpiosinone

O O

O O

OH

O

D

OH

D

43

42 Akaol A

H

HO

45 Salpichrolide J

HO

OH OH

O

44 Salpichrolide C

OH

E

HOOC

HO

OH OH

E

E

OH COOH

H

H

48

HO

E

HO H

HO O

H

H

H

47 Halicloic acid B

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 Table 2

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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) 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) 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) 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) Antiseborrheic (0.790); antihypercholesterolemic (0.764); anti-inflammatory (0.695); radioprotector (0.664) 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) 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) 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) 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) 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) Antineoplastic (0.922); immunosuppressant (0.774); antifungal (0.764); anti-inflammatory (0.757); antiosteoporotic (0.704) 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) 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) 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) Anticonvulsant (0.877); antipruritic (0.728); neuroprotector (0.674); antineoplastic (0.671); hypolipemic (0.656) 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) Antineoplastic (0.782); antibacterial (0.736); apoptosis agonist (0.734); antifungal (0.695); immunosuppressant (0.647) 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) Anti-inflammatory (0.825); apoptosis agonist (0.793); antieczematic (0.748); antineoplastic (0.747); antipruritic (0.714) Antineoplastic (0.884); apoptosis agonist (0.848); immunosuppressant (0.700); antiallergic (0.692); antimitotic (0.617) Antineoplastic (0.799); antiprotozoal (plasmodium) (0.776); apoptosis agonist (0.716); immunosuppressant (0.667) 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) Antineoplastic (0.841); immunosuppressant (0.722); anti-inflammatory (0.675); apoptosis agonist (0.669) Antineoplastic (0.844); apoptosis agonist (0.792); anti-inflammatory (0.780); antipsoriatic (0.667); hypolipemic (0.661) 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)

26

27 28

29 30

31

32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

*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), 6,8pentaen-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

A

B

O

H

H

O

H

NaO3SO

HO

OH

H

HO

50 Equilenin

51 Equilenin sulphate OH

52 17 -Dihydroequilenin

O

53 Estra-1,3,5,7,9-pentaen-17-one

OH

O HO

H

H

HO

HO

54

OH

OH

HO

55

56

OH

H

H

61

C

HO

57

OSO3Na

61

60

59

58

A

H

62

64

63

OH

B

66 Cinanthrenol A

67

68

73

72

71

70

69

74

76 75

E HO

C A 77

78

79

Fig. 3 Di- and triaromatic steroids and terpenoids derived from fungi, invertebrates, sediments, and petroleum

B

D

80

Appl Microbiol Biotechnol (2018) 102:4663–4674 Table 3

4671

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

Predicted biological activities of di- and triaromatic steroids (Pa)* No. 50

51 52

53 54

55

56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80

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) 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) 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) 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) 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) 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) 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) Apoptosis agonist (0.924); antineoplastic (0.868); antiseborrheic (0.847); antioxidant (0.776); neuroprotector (0.728) Antieczematic (0.849); antiosteoporotic (0.837); antiseborrheic (0.830); antineoplastic (0.735); antipruritic (0.696) 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) 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) Apoptosis agonist (0.758); anti-inflammatory (0.744); antineoplastic (0.733); antiseborrheic (0.701) Anti-inflammatory (0.807); antieczematic (0.801); apoptosis agonist (0.746); antineoplastic (0.726); antipruritic (0.699) Antiinfertility, female (0.796); anti-inflammatory (0.794); antineoplastic (0.756); antieczematic (0.750); antipruritic (0.680) Antineoplastic (0.697); ovulation inhibitor (0.683); antiosteoporotic (0.668); antieczematic (0.665); contraceptive (0.613) Antiseborrheic (0.824); prostate disorders treatment (0.699); antieczematic (0.669); anti-inflammatory (0.661) Antiseborrheic (0.827); antineoplastic (0.825); Alzheimer’s disease treatment (0.824) Neurodegenerative diseases treatment (0.809); psychotropic (0.700); alopecia treatment (0.683) Antieczematic (0.767); antidyskinetic (0.670); anti-inflammatory (0.665); antineurotic (0.665); antiseborrheic (0.625) Antieczematic (0.695); anti-inflammatory (0.689); autoimmune disorders treatment (0.652); antineurotic (0.632) Antieczematic (0.767); antidyskinetic (0.670); anti-inflammatory (0.665); antineurotic (0.665); antiseborrheic (0.625) Antieczematic (0.782); antineurotic (0.709); antipruritic (0.641); antiseborrheic (0.620); antipsoriatic (0.619) Neuroprotector (0.685); antiseborrheic (0.651); acute neurologic disorders treatment (0.647); anti-inflammatory (0.595) Hypolipemic (0.724); anticonvulsant (0.649); antieczematic (0.641); anti-inflammatory (0.632); antipruritic (0.621) Antieczematic (0.885); antipsoriatic (0.757); anti-inflammatory (0.735); antipruritic (0.707); neuroprotector (0.680) Antipruritic (0.736); phobic disorders treatment (0.734); antieczematic (0.709); anticonvulsant (0.661); antipsoriatic (0.632) Antieczematic (0.691); antipsoriatic (0.622); psychotropic (0.611); anticonvulsant (0.570); antipruritic (0.560) Apoptosis agonist (0.758); anti-inflammatory (0.744); antineoplastic (0.733); antiseborrheic (0.701) 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) Anti-inflammatory (0.782); antieczematic (0.771); antineoplastic (0.738); antiseborrheic (0.672); apoptosis agonist (0.669) 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) 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 isolated 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)-19norergosta-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 phenanthrene 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 steroid 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 predominant 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-3one, 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 distribution of mono-, di- and triaromatic steroids in various ecological niches, terrestrial, aquatic, and geological. We demonstrated that aromatic steroids exhibit a wide range of biological activities, but mostly they likely possess anticancer, antiinflammatory, neuroprotection, and other activities. The information 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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