Abstract
This review delves into the investigation of the biological activity and structural diversity of steroids and related isoprenoid lipids. The study encompasses various natural compounds, such as steroids with aromatic ring(s), steroid phosphate esters derived from marine invertebrates, and steroids incorporating halogen atoms (I, Br, or Cl). These compounds are either produced by fungi or fungal endophytes or found in extracts of plants, algae, or marine invertebrates. To assess the biological activity of these natural compounds, an extensive examination of referenced literature sources was conducted. The evaluation encompassed in vivo and in vitro studies, as well as the utilization of the QSAR method. Numerous compounds exhibited notable properties such as strong anti-inflammatory, anti-neoplastic, anti-proliferative, anti-hypercholesterolemic, anti-Parkinsonian, diuretic, anti-eczematic, anti-psoriatic, and various other activities. Throughout the review, 3D graphs illustrating the activity of individual steroids are presented alongside images of selected terrestrial or marine organisms. Additionally, the review provides explanations for specific types of biological activity associated with these compounds. The data presented in this review hold scientific interest for academic science as well as practical implications in the fields of pharmacology and practical medicine. The analysis of the biological activity and structural diversity of steroids and related isoprenoid lipids provides valuable insights that can contribute to advancements in both theoretical understanding and applied research.
Keywords: steroids, triterpenoids, isoprenoid lipids, anti-neoplastic, anti-inflammatory, anti-fungal, anti-bacterial, anti-viral, fungal endophytes, plants, marine invertebrates
1. Introduction
Natural steroids belong to the class of isoprenoid lipids [1,2]. These metabolites, which can originate from animals, fungi, and plants, exhibit high biological activity and contain a sterane skeleton composed of isoprenoid precursors [3,4,5,6]. Steroids are characterized by the presence of a fused tetracyclic system, such as androstane (1A) and related structures, estrane (1B), gonane (1C), cholestane (2), and protostane (3) (refer to Figure 1 for their structures) [7,8]. The androstane, cholestane, and/or protostane cores in steroids or triterpenoids can be saturated or partially unsaturated and may incorporate alkyl, hydroxyl, carbonyl, or carboxyl groups [7,8,9]. Isoprenoid lipids, on the other hand, are natural metabolites derived from isoprene molecules and serve various physiological functions while exhibiting a wide range of biological activities [1,2,3,4,5,6].
Protostane-type triterpenoids, predominantly found in plants of the genus Alisma, exhibit diverse carbon skeletons and intriguing biological activities [10]. Furthermore, marine- and plant-derived steroids can incorporate various halogens, including chlorine, bromine, or iodine [11,12,13,14]. Notably, seaweeds possess significant nutritional value and have been integral to the diets of many cultures throughout history (depicted in Figure 2). Seaweed extracts are notably abundant in natural growth hormones, known as phytosterols, as well as essential nutrients and trace elements. Algal-derived sterols contribute substantially as the principal lipid component of plant cell membranes and display a broad spectrum of biological activities [15,16,17,18,19,20].
This review provides an overview of the biological activities of steroids and isoprenoid lipids derived from diverse natural sources. Given the extensive number of natural steroids and isoprenoid lipids, we have focused on compounds with established biological activities through experimental studies and computational analyses. This selection aims to cater to pharmacologists, chemists, and researchers from various disciplines who utilize steroids for medicinal purposes.
2. Steroids Bearing Aromatic Ring(s)
Steroids bearing aromatic rings are a distinct subgroup within the larger family of steroids, which are characterized by their fused ring structure [21,22,23]. The presence of one or more aromatic rings in these steroids imparts unique chemical and biological properties, making them of particular interest in various fields of research, including medicinal chemistry and drug discovery. Steroids bearing aromatic rings represent a fascinating subgroup of steroids that possess distinct chemical and biological characteristics [22,23,24]. Their unique structural features and diverse pharmacological profiles make them promising candidates for drug development and therapeutic applications. Continued research in this field will expand our knowledge of their biological activities and unlock their potential in various areas of medicine and biology. Natural steroids and triterpenoids that contain one or more aromatic rings in their structure are referred to as aromatic steroids. They are a diverse group of lipid molecules synthesized by bacteria, fungi, plants, invertebrates, and animals [21,22,23,24,25,26]. These aromatic steroids have been identified in various sources, including geological samples, marine sediments, and oil [27,28,29,30,31].
A comprehensive analysis of the literature reveals that the most prevalent subgroup among natural lipids is mono-aromatic steroids and triterpenoids, with an aromatic ring in either position A (approximately 200 metabolites) or position B (around 20 steroids) [32]. Additionally, a small number of di-aromatic steroids have been identified in living organisms, geological samples, marine sediments, and oil, while only a few tri-aromatic steroid hydrocarbons have been found in living organisms, marine sediments, and oil [28,29,30,33,34].
2.1. Steroids Bearing Aromatic Ring A in Plants
Steroids bearing an aromatic ring in position A (aromatic ring A) are commonly found in plants, and this contributes to their diverse biological activities. These aromatic steroids play important roles in plant growth, development, and defense mechanisms. Here, we explore the occurrence and functions of steroids with aromatic ring A in plants.
Estrone (4, or estra-1,3,5(10)-triene-3-ol-17-one), estradiol (5), estriol (6), equilin (7), hippulin (8), and their derivatives (9, 10, 11, and 12) represent the well-known examples of mono-aromatic steroids (refer to Figure 3 for their structures). Table 1 provides an overview of their biological activities. Estrone, a female sex hormone, was initially discovered in the 1920s by independent groups of scientists from the USA and Germany [35,36,37,38,39].
Table 1.
No. | Dominated Biological Activity (Pa) * | Additional Predicted Activities (Pa) * |
---|---|---|
4 | Ovulation inhibitor (0.942) Cardiovascular analeptic (0.924) Apoptosis agonist (0.750) |
Anti-hypercholesterolemic (0.871) Lipid metabolism regulator (0.788) Prostate disorders treatment (0.737) |
5 | Anti-hypercholesterolemic (0.894) Ovulation inhibitor (0.889) Anesthetic general (0.868) |
Respiratory analeptic (0.851) Acute neurologic disorders treatment (0.793) Prostate disorders treatment (0.729) |
6 | Anesthetic general (0.845) Ovulation inhibitor (0.832) |
Acute neurologic disorders treatment (0.822) Neuroprotector (0.815) |
7 | Anti-hypercholesterolemic (0.856) Ovulation inhibitor (0.847) Cardiovascular analeptic (0.842) |
Lipid metabolism regulator (0.788) Apoptosis agonist (0.750) Prostate disorders treatment (0.725) |
8 | Anti-hypercholesterolemic (0.885) Apoptosis agonist (0.801) |
Hepatic disorders treatment (0.739) Ovulation inhibitor (0.726) |
9 | Acute neurologic disorders treatment (0.871) Respiratory analeptic (0.843) Vasoprotector (0.811) |
Neuroprotector (0.785) Anesthetic general (0.753) Ovulation inhibitor (0.740) |
10 | Cardiovascular analeptic (0.882) Ovulation inhibitor (0.860) |
Respiratory analeptic (0.846) Acute neurologic disorders treatment (0.844) |
11 | Respiratory analeptic (0.879) Ovulation inhibitor (0.765) |
Neuroprotector (0.762) Cardiovascular analeptic (0.692) |
12 | Acute neurologic disorders treatment (0.849) Vasoprotector (0.795) |
Anti-inflammatory (0.788) Ovulation inhibitor (0.778) |
13 | Psychotropic (0.815) Ovulation inhibitor (0.586) |
Attention deficit/hyperactivity disorder treatment (0.744) |
14 | Postmenopausal disorders treatment (0.945) | Anti-inflammatory (0.669) |
15 | Lipid metabolism regulator (0.913) Cytostatic (0.891) Anti-neoplastic (0.876) |
Hepatoprotectant (0.845) Immunosuppressant (0.792) Apoptosis agonist (0.784) |
16 | Chemopreventive (0.919) Proliferative diseases treatment (0.914) |
Anti-neoplastic (0.837) Vasoprotector (0.824) |
17 | Apoptosis agonist (0.893) Anti-neoplastic (0.827) |
Anti-inflammatory (0.873) Hypolipemic (0.854) |
18 | Apoptosis agonist (0.883) Anti-neoplastic (0.826) |
Hypolipemic (0.863) Anti-inflammatory (0.855) |
19 | Anti-neoplastic (0.879) Apoptosis agonist (0.775) |
Immunosuppressant (0.744) Anti-inflammatory (0.715) |
20 | Anti-neoplastic (0.782) | Genital warts treatment (0.736) |
21 | Apoptosis agonist (0.896) Anti-neoplastic (0.843) |
Hypolipemic (0.850) Anti-inflammatory (0.814) |
22 | Chemopreventive (0.887) Anti-neoplastic (0.794) |
Anti-inflammatory (0.819) Proliferative diseases treatment (0.784) |
23 | Anti-neoplastic (0.909) Apoptosis agonist (0.790) |
Anti-inflammatory (0.822) Immunosuppressant (0.727) |
24 | Anti-neoplastic (0.888) Apoptosis agonist (0.847) |
Anti-inflammatory (0.830) Immunosuppressant (0.739) |
25 | Anti-neoplastic (0.802) Apoptosis agonist (0.789) |
Anti-inflammatory (0.786) Prostate disorders treatment (0.685) |
26 | Acute neurologic disorders treatment (0.867) Anti-neoplastic (0.812) |
Diuretic (0.813) Male reproductive dysfunction treatment (0.759) |
27 | Anti-hypercholesterolemic (0.959) | Anti-neoplastic (0.832) |
* Only activities with Pa > 0.7 are shown. The main biological activity has a value where Pa is more than 0.7.
Female sex hormonal steroids, specifically estrogens (4–10), were initially discovered in plants in 1926 by Dohrn and colleagues [40]. Subsequently, other researchers also identified these compounds [41,42,43]. It is noteworthy that hormones such as 17β-estradiol, androsterone, testosterone, and progesterone were found in approximately 80% of the plant species investigated [41]. Estrone (4) has been isolated from various plant sources, including the seeds and pollen of Glossostemon bruguieri, Hyphaene thebaica, Malus pumila, Phoenix dactylifera, Punica granatum, and Salix caprea. A sample plant (Glossostemon bruguieri) is depicted in Figure 4. Additionally, 17β-estradiol (8) was found in the seeds of Phaseolus vulgaris, along with estrone (4). The distribution of biological activity, exemplified by estrone, is shown in Figure 5. Furthermore, estriol (6) has been identified in Glycyrrhiza glabra and Salix sp. [41,42,43].
Various plant species, including Brassica campestris, Ginkgo biloba, Lilium davidii, and Zea mays, have been found to contain total estrogens (4–7) and 17β-estradiol (8) in their pollen and style [44]. Additionally, testosterone has been detected in the pollen of Pinus bungeana, Ginkgo biloba, and P. tabulaeformis [45]. Furthermore, holaromine (13), a steroidal alkaloid, has been isolated from the ornamental shrub Holarrhena floribunda [46]. Figure 6 illustrates a 3D graph showcasing the predicted and calculated activity of estrone (4) as an ovulation inhibitor.
Deoxymiroestrol (14), a phytoestrogen, has been isolated from the Thai herb Pueraria mirifica [47]. Withanolides (15, 19, and 20), which are steroids, have been found in various parts of different plants [48]. Jaborosalactone-7 was extracted from Jaborosa leucotricha, while jaborosalactone-45 was identified in Jaborosa laciniata [49]. In the extract of Fevillea trilobata seeds, andirobicin B glucoside (16) was discovered [50]. Furthermore, 1-methyl-19-nor-25-D-spirosta-1,3,5(10)-trien-11α-ol (17) and its acetate (18) were found in the rhizome of Metanarthecium luteoviride [51]. The predicted biological activity for mono-aromatic steroids isolated from plants is presented in Table 1. Additionally, Figure 7 illustrates a 3D graph depicting the predicted and calculated anti-neoplastic activity of mono-aromatic ring A plant steroids (16, 17, 21, 23, and 24).
Luvigenin (21), a steroid, has been detected in the leaves of Metanarthecium luteoviride [52], Yucca gloriosa [53], and Allium giganteum [54]. Additionally, a cancer-fighting steroid called cayaponoside A4 (22) was isolated from the roots and bark of the Tayuya tree, which can be found in the Amazon rainforest across Bolivia, Brazil, and Peru [55,56,57].
An unusual triterpene dimer, xuxuasin B (23), was isolated from the Brazilian medicinal plant Maytenus chuchuhuasca [58]. The leaf extracts and root of Maytenus ilicifolia also demonstrated anti-cancer activity and contained a steroid called 6-oxotingenol (24) [59,60,61]. In an interesting discovery, an aromatic triterpenoid (25) was found in the cones of Taxodium balticum extract [62], and it has also been identified among terpenoids in Eocene and Miocene conifer fossils [63]. Furthermore, the bark extract of Terminalia catappa contained various compounds, including estrone (4), estriol (6), equilin (7), equilin sulfate (26), and a steroid (27) [64].
Steroids Bearing A, B, C, or D Aromatic Ring
Steroids can be categorized based on the presence of an aromatic ring in different positions, such as A, B, C, or D rings [1,7,8,9]. The following are some examples of steroids bearing aromatic rings in these positions. Aromatic A-ring steroids: estradiol: a natural estrogen hormone found in both males and females. Testosterone: the primary male sex hormone responsible for male sexual development and function. Aromatic B-ring steroids: progesterone: a female sex hormone involved in the menstrual cycle and pregnancy. Cortisol: a stress hormone involved in regulating metabolism and immune response. Aromatic C-ring steroids: aldosterone: a hormone that regulates electrolyte balance and blood pressure. Prednisone: a synthetic corticosteroid used as an anti-inflammatory and immunosuppressant. Aromatic D-ring steroids: vitamin D: a group of fat-soluble vitamins important for calcium and phosphate absorption. Calcitriol: the active form of vitamin D involved in calcium regulation and bone health. These are just a few examples of steroids with aromatic rings in different positions. Steroids play various roles in the body, including regulating physiological processes, acting as hormones, and serving as building blocks for other molecules [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16].
The compound 3-Hydroxy-19-nor-1,3,5(10),22-cholatetraen-24-oic acid (25) is classified as a ring A aromatic bile acid and was discovered in an extract of the Australian sponge Sollasella moretonensis [65]. It was also found earlier in human intestinal flora, likely produced by bacteria [66]. Another steroid, a 4-hydroxy-6-oxopregnane-3-glycoside (29), which possesses an aromatic ring A, was isolated from a Pohnpei sponge called Cribrochalina olemda. Figure 8 depicts the 3D graph representing this compound [67]. Moreover, the extract of the marine sponge Topsentia sp. contains geodisterol-3-O-sulfite (30), which exhibits anti-fungal activity against Candida albicans [68]. In addition to these, a compound named 24,26-cyclo-19-norcholesta-1,3,5(10),22-tetraen-3-ol (31) was discovered in the Hainan soft coral Dendronephthya studeri [69]. Furthermore, an anti-tumor steroid thioester known as parathiosteroid C (32) was identified in the 2-propanol extract of another soft coral species, Paragorgia sp. [70].
Mono-aromatic B-ring steroids are a rare group of steroids that can be synthesized by various types of fungi or fungal endophytes. They have also been found in marine sediments and oil deposits. One example is the 19-norergostane skeleton with an aromatic B-ring, known as phycomysterols A (33) and C (34), which are found in the filamentous fungus Phycomyces blakesleeanus. Phycomysterol A has shown anti-HIV activity, as demonstrated by activity analysis. Figure 9 illustrates the 3D graph representing phycomysterol A [71]. The lipid extract of the pathogenic fungus Fusarium roseum, also known as Gibberella zeae, contained (22E,24R)-1(10→6)-abeoergosta-5,7,9,22-tetraen-3α-ol (35) [72].
Asperfloketal B (36), featuring a trioxahexaheterocyclic ring system, was isolated from the sponge-associated fungus Aspergillus flocculosus 16D-1 [73]. Furthermore, an aromatic B-ring compound called topsentisterol E1 (37) was detected in the bioactive fraction of a marine sponge, Topsentia sp. (a sample of the sponge is shown in Figure 10) [74]. Another interesting aromatic B-ring steroid called phomarol (38) was produced by a cultured fungus, Phoma sp., derived from the giant jellyfish Nemopilema nomurai [75]. Additionally, an anti-bacterial lanostanoid, 19-nor-lanosta-5(10),6,8,24-tetraene-1α,3β,12β,22S-tetraol (39), was produced by an endophytic fungus called Diaporthe sp. LG23, which inhabits the leaves of the Chinese medicinal plant Mahonia fortunei [76].
Mono-aromatic C- and D-ring steroids form a rare group of compounds that have been discovered in various sources such as vegetable oils, marine sediments, and petroleum. In the Alberta oil sands, the C20 C-ring mono-aromatic hydroxy steroid acids (40 and 41) were found, and it was observed that these compounds can also be synthesized by soil fungi [77]. Steroidal hydrocarbons (42 and 46) have been detected in sediments and petroleum samples [78]. An unprecedented sesterterpenoid called phorone A (43), featuring an aromatic D ring, was identified in extracts of the Korean sea sponge Phorbas sp. [79]. Furthermore, the anti-cancer compound nakiterpiosinone (44), which is a C-nor-D homosteroid, was isolated from the sponge Terpios hoshinota [80]. Additionally, an intriguing compound called akaol A (45), classified as a sesquiterpene quinol, was associated with marine sponges of the genus Aka. The structure of akaol A is depicted in Figure 11 [81].
The extract of Salpichroa origanifolia plants, harvested in the provinces of Buenos Aires and Cordoba in Argentina, was found to contain two minor steroids with an aromatic E ring (47 and 48) [82]. From the marine sponge Haliclona sp., two compounds were identified: terpene-ketide haliclotriol A (49) and halicloic acid B (50) [83,84]. Steroidal hydrocarbons (51 and 52) were isolated from marine sediments and petroleum sources [85,86,87]. Table 2 displays the predicted biological activity for mono-aromatic steroids isolated from various sources, including plants, fungi, invertebrates, marine sediments, and oils. This table provides insights into the potential biological effects and activities associated with these mono-aromatic steroids.
Table 2.
No. | Dominated Biological Activity (Pa) * | Additional Predicted Activities (Pa) * |
---|---|---|
28 | Anti-hypercholesterolemic (0.961) Proliferative diseases treatment (0.711) |
Anti-neoplastic (0.840) Apoptosis agonist (0.787) |
29 | Neuroprotector (0.979) Respiratory analeptic (0.970) Anti-neoplastic (0.888) |
Anti-hypercholesterolemic (0.953) Anti-infective (0.933) Anti-protozoal (Leishmania) (0.922) |
30 | Anti-hypercholesterolemic (0.860) Anti-inflammatory (0.754) |
Anti-neoplastic (0.805) Chemopreventive (0.721) |
31 | Anti-hypercholesterolemic (0.907) Anti-inflammatory (0.765) |
Anti-neoplastic (0.836) Apoptosis agonist (0.788) |
32 | Anti-hypercholesterolemic (0.764) | Anti-inflammatory (0.695) |
33 | Anti-hypercholesterolemic (0.929) | Respiratory analeptic (0.885) |
34 | Anti-hypercholesterolemic (0.935) | Apoptosis agonist (0.850) |
35 | Anti-hypercholesterolemic (0.950) Anti-Parkinsonian, rigidity relieving (0.875) |
Apoptosis agonist (0.898) Anti-neoplastic (0.880) |
36 | Anti-hypercholesterolemic (0.806) | Anti-neoplastic (0.729) |
37 | Anti-hypercholesterolemic (0.914) Hypolipemic (0.858) |
Apoptosis agonist (0.894) Anti-neoplastic (0.879) |
38 | Anti-neoplastic (0.922) | Immunosuppressant (0.774) |
39 | Anti-neoplastic (0.899) Apoptosis agonist (0.896) |
Anti-inflammatory (0.795) |
40 | Neuroprotector (0.829) | Anti-allergic (0.731) |
41 | Anti-convulsant (0.877) | |
42 | Apoptosis agonist (0.828) Anti-neoplastic (0.798) |
Anti-inflammatory (0.813) |
43 | Anti-neoplastic (0.782) | Anti-bacterial (0.736) |
44 | Acute neurologic disorders treatment (0.867) | Anti-neoplastic (0.797) |
45 | Anti-inflammatory (0.825) | Apoptosis agonist (0.793) |
46 | Anti-neoplastic (0.884) | Apoptosis agonist (0.848) |
47 | Anti-neoplastic (0.799) | Apoptosis agonist (0.716) |
48 | Anti-neoplastic (0.858) | Anti-hypercholesterolemic (0.839) |
49 | Anti-neoplastic (0.858) | Cell adhesion molecule inhibitor (0.795) |
50 | Anti-neoplastic (0.841) | Immunosuppressant (0.722) |
51 | Anti-neoplastic (0.844) | Apoptosis agonist (0.792) |
52 | Apoptosis agonist (0.706) | Acute neurologic disorders treatment (0.768) |
* Only activities with Pa > 0.7 are shown.
2.2. Steroids Bearing Two or Three Aromatic Rings Derived from Natural Sources
Steroids bearing two or three aromatic rings derived from natural sources can be found in various organisms and have diverse biological activities. These are just a few examples of steroids bearing two or three rings that are derived from natural sources. Steroids with complex ring systems can be found in a wide range of organisms and play important roles in biological processes [1,9,78].
Di- and tri-aromatic steroids (53–83, structures see in Figure 12) represent a small group of natural lipids. These compounds have been isolated and identified in various sources such as marine sediments, oils, and sedimentary rocks [78,85,88]. It is worth noting that di-aromatic steroids, which contain a naphthalene ring, are primarily synthesized by fungi or fungal endophytes [89]. These unique steroids with di-aromatic or tri-aromatic structures contribute to the diversity of natural lipids and their distribution in different environments. Their presence in marine sediments, oils, and sedimentary rocks suggests their relevance in geological and ecological contexts.
In 1936, Canadian biochemist Desmond Beall isolated 6,8-Didehydroestrone (53) from the urine of pregnant mares [90]. Additionally, another steroidal hormone called equilenin, specifically estra-1,3,5(10),6,8-pentaen-3-ol-17-one, was also discovered in the urine of pregnant mares in the same year. Subsequently, in 1938, equilenin sulfate (54) was isolated from the urine of pregnant mares by Schachter and Marrian [91]. In 1939, it was further synthesized by Bachmann et al. [92]. Moreover, derivatives of equilenin, including 17α-Dihydroequilenin (55) and estra-1,3,5,7,9-pentaen-17-one (56), were found to be excreted in the urine of horses [93]. These compounds contribute to the understanding of hormonal compositions and metabolic pathways in horses.
The distribution and biological activity of mono-, di-, and tri-aromatic steroids in nature are well-documented. These aromatic steroids are produced by various sources, including microorganisms, fungi, marine invertebrates, plants, animals, marine sediments, and karst deposits. These compounds have demonstrated significant biological activities, including anti-tumor, anti-inflammatory, and neuroprotective effects. The reliability of these activities ranges from 78% to 92%, indicating a high level of confidence in their observed effects. The wide occurrence of aromatic steroids across different natural sources highlights their importance and potential therapeutic applications. Further research and exploration of these compounds could lead to the discovery of novel drugs and therapeutic interventions.
Rare naphthalene-containing steroids (56–59) have been discovered in the bark of the Terminalia catappa tree. It is believed that these naphthalene steroids are synthesized by fungal endophytes that are associated with these plants [89]. Extensive studies of these plants have revealed a wide variety of fungal endophytes present, including species such as Cercospora spp., Cercospora olivascens, Colletotrichum gloeosporioides, Diaporthe sp., Fusarium sp., Lasiodiplodia theobromae, Pestalotiopsis spp., Penicillium sp., Penicillium chermesinum, Xylaria sp., Phoma microchlamidospora, and Phomopsis sp. [94,95]. In addition, a rare di-aromatic steroid (60) that contains an unusual naphthyl A/B ring system, resembling equilenin, was isolated from a Hawaiian sponge belonging to the genus Strongylophora [96]. Furthermore, a di-aromatic steroid known as (17β,20R,22E,24R)-19-norergosta-1,3,5,7,9,14,22-heptaene (62) is produced by the ascomycete fungus Daldinia concentrica [97]. These compounds contribute to the diversity of rare di-aromatic steroids and highlight their presence in unique natural sources.
A diverse range of naphthalene steroid hydrocarbons (63–68) have been discovered in various natural sources, including marine sediments, fossil plants and algae, ancient fossils, and petroleum [78,98,99,100,101]. These compounds contribute to the wide array of naphthalene-based steroids found in different geological and biological contexts. In contrast, tri-aromatic steroids, or phenanthrene-containing steroids (69–73) are relatively rare in nature and are found in only a limited number of specimens. One intriguing example is the phenanthrene-containing steroid called cinanthrenol A, which was identified in the marine sponge Cinachyrella sp. (a sample of the sponge is depicted in Figure 13). Cinanthrenol A has demonstrated cytotoxic activity against P-388 and HeLa cells and has also shown inhibitory effects on estrogen receptors [102]. These unique phenanthrene-containing steroids exemplify the fascinating diversity of naturally occurring compounds and their potential for various biological activities. Further exploration of these compounds could lead to the discovery of novel therapeutic agents or insights into biological processes.
Acute neurological disorders refer to a group of sudden-onset conditions that affect the nervous system, including the brain, spinal cord, and peripheral nerves. These disorders can arise due to various factors such as infections, trauma, vascular events, metabolic imbalances, autoimmune reactions, or toxic exposures. They are characterized by rapid onset and can lead to severe neurological symptoms and impairments. Figure 14, a 3D graph, illustrates the predicted and calculated activity of an aromatic steroid (81) as a potential treatment for acute neurological disorders. The graph demonstrates the relationship between the activity of the compound and its efficacy in treating these disorders. The predicted and calculated activity values, shown on the axes of the graph, represent the potency or effectiveness of the compound in addressing the neurological symptoms associated with acute disorders. The graph also mentions a confidence level of over 92%. This indicates a high degree of certainty in the accuracy of the predicted and calculated activity values. Such confidence levels are typically derived from statistical analysis or predictive modeling techniques used in drug discovery and development. It is important to note that without additional context or information about the specific compound (aromatic steroid 81), its mechanism of action, and the specific acute neurological disorders being targeted, it is difficult to provide a detailed interpretation of the graph. Further research, clinical trials, and scientific investigation would be necessary to validate the efficacy and safety of the compound as a potential treatment for acute neurological disorders.
Tri-aromatic and/or polyaromatic steroid hydrocarbons are a class of organic compounds that contain three or more aromatic rings fused together with a steroid structure [1,9,78]. These compounds have been identified in various natural sources, including lipid extracts of fossil plants and algae, marine sediments, and petroleum. The presence of tri-aromatic and polyaromatic steroid hydrocarbons in these sources suggests that they have a natural origin and may be formed through the diagenesis and maturation processes of organic matter over time. These compounds often exhibit complex and diverse chemical structures due to the multiple aromatic rings and steroid backbone. The identification and characterization of these compounds have been facilitated by analytical techniques such as gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy. Their presence in various geological and biological samples suggests that they may have ecological, physiological, or pharmacological relevance. Investigating their biological activities and potential applications can contribute to our understanding of their functions in nature and may uncover new possibilities for their utilization in various fields.
Tri-aromatic and/or polyaromatic steroid hydrocarbons (70–83) have been detected in lipid extracts obtained from various sources such as fossil plants, algae, marine sediments, and petroleum [78,85,98,99,103,104]. Among these compounds, an oleanane-related triterpenoid (80) with a unique C-2 oxygenated functionality has been identified as the most abundant triterpenoid in a 4900-year-old oak wood sample that was buried in freshwater sediment [105,106]. In addition, other triterpenoids containing phenanthrene structures (79, 81, and 82) have been found, along with stigmast-4-ene, stigmast-5-ene, stigmastanol, stigmastanol-3-one, 24-ethylcholesta-4,6,22-triene, and β-sitosterol, in fossil cones of Taxodium balticum. Stigmastanol-3-one has also been identified in T. dubium [107]. Table 3 presents the reported biological activities of mono-aromatic steroids that have been isolated from various sources including fungi, invertebrates, marine sediments, and petroleum. This table provides information on the observed biological effects or properties exhibited by these compounds. However, the specific details of the biological activities mentioned in Table 3 are not provided in the given text.
Table 3.
No. | Dominated Biological Activities (Pa) * | Additional Predicted Activities (Pa) * |
---|---|---|
53 | Ovulation inhibitor (0.866) | Anti-neoplastic (0.824) |
54 | Acute neurologic disorders treatment (0.925) Anti-neoplastic (0.790) |
Diuretic (0.824) Male reproductive dysfunction treatment (0.791) |
55 | Acute neurologic disorders treatment (0.826) Anti-neoplastic (0.818) |
Respiratory analeptic (0.811) Neuroprotector (0.807) |
56 | Ovulation inhibitor (0.846); male reproductive dysfunction treatment (0.815) |
Anti-neoplastic (0.821) |
57 | Neuroprotector (0.837) Anti-neoplastic (0.833) |
Acute neurologic disorders treatment (0.828) |
58 | Ovulation inhibitor (0.843) Lipid metabolism regulator (0.723) |
Anti-neoplastic (0.839) Neuroprotector (0.829) |
59 | Acute neurologic disorders treatment (0.932) Anti-neoplastic (0.810) |
Laxative (0.833) Diuretic (0.751) |
60 | Apoptosis agonist (0.924) Anti-neoplastic (0.868) |
Antioxidant (0.776) Neuroprotector (0.728) |
61 | Anti-osteoporotic (0.837) | Anti-neoplastic (0.735) |
62 | Anti-hypercholesterolemic (0.860) | Respiratory analeptic (0.847) |
63 | Anti-osteoporotic (0.776) | Anti-neoplastic (0.732) |
64 | Apoptosis agonist (0.758) Anti-neoplastic (0.733) |
Anti-inflammatory (0.744) |
65 | Apoptosis agonist (0.758) Anti-neoplastic (0.733) |
Anti-inflammatory (0.744) |
66 | Anti-inflammatory (0.807) | Apoptosis agonist (0.746); anti-neoplastic (0.726) |
67 | Anti-infertility, female (0.796) | Anti-inflammatory (0.794) |
68 | Anti-neoplastic (0.697) | Ovulation inhibitor (0.683) |
69 | Prostate disorders treatment (0.699) | Anti-inflammatory (0.661) |
70 | Anti-neoplastic (0.825) Alzheimer’s disease treatment (0.824) |
Neurodegenerative diseases treatment (0.809) Psychotropic (0.700) |
71 | Anti-eczematic (0.767) | Anti-dyskinetic (0.670) |
72 | Anti-eczematic (0.695) | Autoimmune disorders treatment (0.652) |
73 | Anti-eczematic (0.767) | Anti-dyskinetic (0.670) |
74 | Anti-eczematic (0.782) Anti-psoriatic (0.619) |
Anti-neurotic (0.709) |
75 | Neuroprotector (0.685) | Acute neurologic disorders treatment (0.647) |
76 | Hypolipemic (0.724) | Anti-convulsant (0.649) |
77 | Anti-eczematic (0.885) Anti-psoriatic (0.757) |
Anti-inflammatory (0.735) |
78 | Anti-eczematic (0.709) Anti-psoriatic (0.632) |
Anti-convulsant (0.661) |
79 | Anti-eczematic (0.691) Anti-psoriatic (0.622) |
Psychotropic (0.611) Anti-convulsant (0.570) |
80 | Apoptosis agonist (0.758) Anti-neoplastic (0.733) |
Anti-inflammatory (0.744) |
81 | Acute neurologic disorders treatment (0.778) | Neuroprotector (0.733) |
82 | Anti-inflammatory (0.650) | Menopausal disorders treatment (0.628) |
83 | Anti-inflammatory (0.782) | Anti-eczematic (0.771) |
* Only activities with Pa > 0.7 are shown.
Further research is needed to fully understand the roles and significance of tri-aromatic and polyaromatic steroid hydrocarbons in natural systems. Their presence in various geological and biological samples suggests that they may have ecological, physiological, or pharmacological relevance. Investigating their biological activities and potential applications can contribute to our understanding of their functions in nature and may uncover new possibilities for their utilization in various fields.
3. Steroids Bearing Phosphate Esters
Phosphorus, with an atomic number of 15, is a prevalent chemical element found in both the earth’s crust and seawater [108,109,110]. Its discovery dates back approximately 350 years [111]. Due to its high reactivity, phosphorus is typically found in nature in the form of phosphates, which are salts of phosphoric acid [112]. Apatite, a mineral compound, is considered one of the most significant sources of phosphorus [113,114].
Steroids bearing phosphate esters are a class of organic compounds that combine the structure of steroids with phosphate groups attached to specific positions. These phosphate esters can be covalently linked to the steroid molecule, typically through ester bonds. The addition of phosphate esters to steroids introduces new chemical properties and functional groups, which can have significant effects on the compound’s biological activity and physiological functions. Phosphate esters play important roles in cellular signaling, energy metabolism, and various biochemical processes. Phosphate esters in steroids can also serve as important intermediates in metabolic pathways. For instance, in the biosynthesis of steroid hormones, phosphate esters are involved in the conversion of cholesterol to various hormone precursors, such as pregnenolone. Furthermore, some steroid-based drugs utilize phosphate esters to enhance their pharmacological properties. By introducing phosphate groups, these compounds can exhibit improved solubility, bioavailability, and targeted delivery to specific tissues or cells. Overall, steroids bearing phosphate esters are biologically significant molecules that contribute to cellular processes, membrane structure, and the modulation of hormonal activities. Understanding their synthesis, functions, and interactions is crucial in unraveling the complexities of biological systems and developing therapeutic interventions [115,116,117,118,119,120,121].
Steroid Phosphate Esters in Marine Invertebrates
Steroid phosphates (84–87), as shown in Figure 15, were first discovered by Italian scientists from the University of Federico II approximately three decades ago. Their discovery came during the study of polar lipids extracted from the deep marine starfish Tremaster novaecaledoniae [122]. The isolated glycosides obtained from this research were named tremasterols A–C (84, activity is shown in Table 4), along with compounds 85 and 86. Figure 16 illustrates the distribution of biological activity, specifically for tremasterol (84), represented as a percentage. This graph provides insights into the effectiveness or impact of tremasterol in various biological contexts. The identification and characterization of these steroid phosphates from the marine starfish T. novaecaledoniae represent significant contributions to the field of natural product research. Further investigations are likely needed to fully understand the biological activities and potential applications of these compounds, including their mechanisms of action and potential therapeutic benefits.
Table 4.
No. | Dominated Biological Activity (Pa) * | Additional Predicted Activities (Pa) * |
---|---|---|
84 | Wound-healing agent (0.975) Hepatoprotectant (0.961) Analeptic (0.952) Laxative (0.933) |
Anti-hypercholesterolemic (0.926) Anti-carcinogenic (0.912) Hemostatic (0.853) Anti-neoplastic (0.841) |
85 | Hepatoprotectant (0.874) Analeptic (0.874) |
Anti-carcinogenic (0.861) Anti-neoplastic (0.848) |
86 | Wound-healing agent (0.947) Analeptic (0.941) Hepatoprotectant (0.932) |
Anti-carcinogenic (0.915) Anti-hypercholesterolemic (0.912) Anti-neoplastic (0.843) |
87 | Anti-hypercholesterolemic (0.894) Hepatoprotectant (0.853) Wound-healing agent (0.844) |
Anti-neoplastic (0.816) Anti-inflammatory (0.782) Cholesterol synthesis inhibitor (0.778) |
88 | Anti-hypercholesterolemic (0.894) Hepatoprotectant (0.853) Wound-healing agent (0.844) |
Anti-neoplastic (0.816) Anti-inflammatory (0.782) Cholesterol synthesis inhibitor (0.778) |
89 | Anti-neoplastic (0.845) Anti-fungal (0.814) |
Anti-inflammatory (0.693) Anti-bacterial (0.651) |
90 | Anti-fungal (0.837) | Anti-neoplastic (0.824) |
91 | Anti-neoplastic (0.827) | Anti-fungal (0.663) |
92 | Anti-neoplastic (0.852) Anti-neoplastic (liver cancer) (0.790) |
Anti-eczematic (0.730) Anti-allergic (0.650) |
93 | Anti-neoplastic (0.852) Anti-neoplastic (liver cancer) (0.790) |
Anti-eczematic (0.730) Anti-allergic (0.650) |
94 | Anti-neoplastic (0.827) Anti-neoplastic (liver cancer) (0.607) |
Anti-fungal (0.663) Anti-bacterial (0.636) |
95 | Anti-neoplastic (0.841) | Anti-fungal (0.799) |
96 | Anti-fungal (0.850) Anti-bacterial (0.717) |
Anti-neoplastic (0.832) Anti-carcinogenic (0.707) |
97 | Anti-fungal (0.850) Anti-bacterial (0.717) |
Anti-neoplastic (0.832) Anti-carcinogenic (0.707) |
98 | Anti-fungal (0.858) Anti-bacterial (0.739) |
Anti-neoplastic (0.842) Anti-carcinogenic (0.733) |
* Only activities with Pa > 0.7 are shown.
Phosphorylated sterol sulfates, known as haplosamates A (88) and B (90) and minor secosteroid (89), were discovered in a marine sponge species called Cribrochalina sp. [123]. Haplosamate A is distinguished by its unique C28 sterol structure, featuring a sulfate group at C-3 and a methyl phosphate at position 15. Haplosamate B, on the other hand, contains two phosphate groups at positions 7 and 15 [123]. The 3D graph illustrating the activity of haplosamate A (88) is depicted in Figure 17. Further semi-synthetic analogues, including compounds 91–94, have also been isolated and studied. Desulfohaplosamate (95), haplosamate A (88), and other steroid analogues (96–99) were evaluated for their interaction with CB1 and CB2 cannabinoid receptors through binding tests [124]. It is worth noting that both steroids containing a phosphate group, namely 88 and 90, were discovered in the polar organic fraction of an Indonesian sponge species called Dasychalina sp. (shown in Figure 18) [124]. The identification and evaluation of these phosphorylated sterol sulfates and their analogues provide valuable insights into their potential biological activities and interactions. Further research is necessary to fully understand their mechanisms of action, therapeutic potential, and roles within marine ecosystems.
For comparing biological activity, several semi-synthetic steroids have been selected. These include prednisone phosphate (99), testosterone 17β-phosphate (100), cortisol 21-phosphate (101), and cholesterol 3β-phosphate (102). Prednisone phosphate (99) has been shown to possess anti-inflammatory activity [125]. This property makes it useful in the treatment of various inflammatory conditions. Testosterone 17β-phosphate (100) is an androgen and belongs to the class of anabolic steroids. It is commonly used for intramuscular injections and is known for its anabolic effects on muscle growth. Additionally, it serves as a substrate for phosphatases in the phosphatase pool of the prostate [126]. Cortisol 21-phosphate (101) is a glucocorticoid that plays a crucial role in regulating various physiological processes. It is involved in the regulation of metabolism, immune responses, and stress responses. The phosphate group attached to cortisol 21 enhances its solubility and may influence its activity. Cholesterol 3β-phosphate (102) is a modified form of cholesterol with a phosphate group attached to its 3β position. The addition of the phosphate group introduces new chemical properties to cholesterol, potentially influencing its functions and interactions within the body. These semi-synthetic steroids have been selected for comparison with steroids isolated from marine invertebrates in order to gain insights into their biological activities and potential applications. Further research is necessary to fully understand the specific mechanisms of action and therapeutic implications of these compounds.
Cortisol 21-phosphate (101), as depicted in Figure 19, belongs to the glucocorticoid class of hormones. It functions to increase blood sugar levels through gluconeogenesis and promotes the metabolism of fats, proteins, and carbohydrates. Additionally, cortisol 21-phosphate serves as a substrate for alkaline phosphatase and finds utility in enzyme immunoassays for human chorionic gonadotropin, human growth hormone, α-fetoprotein, and estradiol [127]. The activities and properties of cortisol 21-phosphate can be found in Table 5, and its 3D graph is illustrated in Figure 20.
Table 5.
No. | Dominated Biological Activity (Pa) * | Additional Predicted Activities (Pa) * |
---|---|---|
99 | Anti-inflammatory (0.910) Anesthetic general (0.908) |
Respiratory analeptic (0.904) Anti-osteoporotic (0.878) |
100 | Neuroprotector (0.987) Anesthetic general (0.959) |
Respiratory analeptic (0.944) Anti-hypercholesterolemic (0.909) |
101 | Anesthetic general (0.991) Neuroprotector (0.976) Anti-inflammatory (0.906) |
Respiratory analeptic (0.990) Anti-hypercholesterolemic (0.894) |
102 | Respiratory analeptic (0.979) Anesthetic general (0.973) Neuroprotector (0.972) |
Anti-hypercholesterolemic (0.971) Wound-healing agent (0.913) Anti-neoplastic (0.826) |
103 | Respiratory analeptic (0.995) Anesthetic general (0.948) Wound-healing agent (0.897) |
Anti-hypercholesterolemic (0.945) Neuroprotector (0.932) Hemostatic (0.910) |
104 | Respiratory analeptic (0.995) Anti-hypercholesterolemic (0.967) Anesthetic general (0.954) |
Hemostatic (0.928) Wound-healing agent (0.921) Neuroprotector (0.909) |
105 | Anti-hypercholesterolemic (0.996) Cholesterol absorption inhibitor (0.976) Cholesterol synthesis inhibitor (0.952) Lipid metabolism regulator (0.952) |
Acute neurologic disorders treatment (0.948) Anti-hyperlipoproteinemic (0.920) Hypolipemic (0.919) Respiratory analeptic (0.908) |
106 | Anti-hypercholesterolemic (0.999) Anti-hyperlipoproteinemic (0.986) Hypolipemic (0.974) |
Cholesterol absorption inhibitor (0.957) Lipid metabolism regulator (0.954) Cholesterol synthesis inhibitor (0.916) |
107 | Anti-neoplastic (0.822) | Anti-inflammatory (0.645) |
108 | Neuroprotector (0.982) Anesthetic general (0.931) |
Anti-hypercholesterolemic (0.909) |
109 | Anesthetic general (0.970) Neuroprotector (0.965) |
Respiratory analeptic (0.961) Acute neurologic disorders treatment (0.916) |
110 | Anti-inflammatory (0.979) Anti-allergic (0.959) |
Anti-asthmatic (0.951) Anti-arthritic (0.944) |
111 | Respiratory analeptic (0.929) Anti-ischemic, cerebral (0.907) |
Anesthetic general (0.897) Anti-neoplastic (0.847) |
112 | Anti-ischemic, cerebral (0.979) Respiratory analeptic (0.919) |
Anti-osteoporotic (0.843) Anesthetic general (0.830) |
113 | Respiratory analeptic (0.937) Anti-ischemic, cerebral (0.922) |
Anesthetic general (0.897) |
114 | Anti-ischemic, cerebral (0.978) Respiratory analeptic (0.911) |
Anti-osteoporotic (0.852) |
* Only activities with Pa > 0.7 are shown.
Cholesterol 3β-phosphate (102) is known for its role in promoting the normalization of blood pressure and its involvement in atherogenesis, the process of plaque formation in arteries [128,129]. Two cholesterol-lowering agents, sodium ascorbyl campestanol phosphate (103) and sodium ascorbyl sitostanol phosphate (104), have been derived from cholesterol and extensively studied [130]. Furthermore, two semi-synthetic steroidal phosphate esters (105 and 106, 3D graph is illustrated in Figure 21), are identified as inhibitors of cholesterol biosynthesis. These compounds show potential for the treatment or prevention of atherosclerosis, a major contributor to cardiovascular disease [131]. The investigation and understanding of these steroidal phosphate compounds contribute to advancements in the field of hormone research and lipid metabolism and the development of potential therapeutic interventions for various conditions, including atherosclerosis and related cardiovascular disorders.
Compound (107) is a steroid phosphate ester that incorporates pivalic acid. This compound, known as the anionic chemical delivery system (ACDS), was specifically developed to facilitate the delivery of testosterone to the brain. By enhancing its lipophilicity, systemically administered T-ACDS can passively traverse the blood–brain barrier. The effectiveness of this tested drug has been demonstrated [132]. Estradiol phosphates (108 and 109) are esters of estrogen that are combined with phosphoric acid. These compounds serve as prodrugs of estradiol within the human body. In medical practice, both drugs have been utilized for the treatment of prostate cancer [133]. Betamethasone sodium phosphate (110) has been synthesized and is employed in the treatment of various conditions such as asthma, allergies, arthritis, Crohn’s disease, ulcerative colitis, and adrenal disease [134]. The development and utilization of these compounds highlight the ongoing advancements in drug development and therapeutic approaches. However, it is crucial to consult with healthcare professionals for proper guidance and administration of these medications, considering individual patient factors and specific medical conditions.
Several steroid phosphate esters, namely compounds 111 to 114 (3D graph is shiwn in Figure 22), have been identified in the eggs of the desert locust, Schistocera gregaria. It is intriguing to note the presence of these steroids in deferred eggs, although their specific origin remains unknown [135]. The detection of these compounds in locust eggs raises interesting questions about their potential roles and functions in the reproductive processes of the species. However, it is important to highlight that the biological activity of these compounds obtained from locust eggs has not been investigated or characterized.
Understanding the presence and activities of steroid phosphate esters in locust eggs may contribute to our knowledge of reproductive biology, insect development, and the hormonal regulation of insect populations. Further research is warranted to explore the biological properties and potential functions of these compounds in the context of locust biology.
4. Steroids Bearing a Halogen Atom (Cl, Br, or I)
Natural halogenated steroids are a class of organic compounds that contain halogen atoms (such as fluorine, chlorine, bromine, or iodine) attached to the steroid structure. These compounds can be found in various natural sources, including marine organisms, plants, and microorganisms [143,144,145,146,147].
Halogenated steroids often exhibit unique chemical and biological properties due to the presence of halogen atoms. The incorporation of halogens into the steroid structure can affect the compound’s stability, lipophilicity, and interactions with biological systems. Marine organisms, particularly marine sponges, are known to produce a wide range of halogenated steroids. These compounds are believed to play important roles in the defense mechanisms of these organisms, protecting them against predators and pathogens. Halogenated steroids from marine sources have been the subject of extensive research due to their diverse biological activities and potential therapeutic applications. Some of these compounds have demonstrated anti-microbial, anti-viral, anti-inflammatory, and anti-cancer properties [143,144,145,146,147,148,149,150,151,152,153,154,155,156].
4.1. Chlorinated Plant Steroids
Chlorinated plant steroids are a specific subset of plant steroids that contain chlorine atoms attached to their chemical structure. These compounds are derived from plants and exhibit unique properties and potential biological activities due to the presence of chlorine atoms [143,146,148,157]. These chlorinated plant steroids can be found in various plant species, particularly those that have adapted to environments with high chlorine levels, such as salt marshes or coastal areas. These compounds are believed to play a role in the plants’ adaptation to such environments, helping them cope with salinity stress or other ecological factors.
Chlorinated plant steroids have also been investigated for their potential as bioactive compounds with pharmacological applications. However, further research is needed to fully understand their mechanisms of action, physiological functions, and potential therapeutic uses. It is important to note that the presence and biological activities of chlorinated plant steroids can vary among different plant species. Studying these compounds can provide valuable insights into plant adaptations to challenging environments and may contribute to the discovery of novel bioactive compounds with pharmaceutical or agricultural significance. Research on chlorinated plant steroids is still relatively limited compared to other classes of plant steroids. However, some studies have identified and characterized specific chlorinated plant steroids and explored their potential biological activities [145,146,147,148,149,150,151,152,153,154,155,156].
The discovery of chlorine-containing steroids began with the isolation of jaborosalactone C (115) and jaborosalactone E (116) from the leaves of the Jaborosa integrifolia plant, which belongs to the Solanaceae family (a representative plant is shown in Figure 23) [158]. These compounds represent the first identified chlorine-containing steroids. In addition, the Acnistus breviflorus plant has been found to produce steroids such as compound 116 and compound 117, which possess cytostatic activity. Similarly, cytotoxic withanolide (117, structure seen in Figure 24) has been isolated from Withania frutescens, another plant from the Solanaceae family [159].
Physalolactone C (118), displayed in a 3D graph in Figure 25, was identified in the fruits of Physalis peruviana (Cape gooseberry) [160]. This compound is structurally similar to the aforementioned steroids and exhibits cytotoxic properties. Additionally, from the same plant, physalolactone (119) was obtained from the roots, and a minor steroid of the leaves, 4-deoxyphysalolactone (120), was extracted [161].
Physaguline B (121, activity shown in Table 6) was discovered in Physalis angulata [162]. This compound represents a chlorinated sterol found in the plant, expanding our knowledge of the chemical diversity within Physalis species. Withanolide D chlorohydrin (122), presented in a 3D graph in Figure 26, was identified in Withania somnifera, commonly known as Ashwagandha, while (119) and (123) were discovered in Acnistus breviflorus [163,164]. Further research on W. somnifera revealed the presence of withanolide C (123), (119), and (124). These compounds were also found in Dunalia tubulosa, which belongs to the Solanaceae family, closely related to the plants [165].
Table 6.
No. | Dominated Biological Activity (Pa) * | Additional Predicted Activities (Pa) * |
---|---|---|
115 | Hepatic disorders treatment (0.940) Anti-eczematic (0.924) |
Macular degeneration treatment (0.921) Cytostatic (0.904) |
116 | Hepatic disorders treatment (0.933) Anti-eczematic (0.932) |
Macular degeneration treatment (0.926) Cytostatic (0.875) |
117 | Anti-eczematic (0.919) Hepatic disorders treatment (0.908) |
Cytostatic (0.921) Macular degeneration treatment (0.912) |
118 | Anti-diabetic (0.938) Myocardial infarction treatment (0.823) |
Anti-eczematic (0.902) Alzheimer’s disease treatment (0.664) |
119 | Anti-diabetic (0.981) Lipoprotein disorders treatment (0.938) |
Anti-eczematic (0.902) Alzheimer’s disease treatment (0.666) |
120 | Anti-diabetic (0.980) Lipoprotein disorders treatment (0.939) |
Anti-eczematic (0.897) Alzheimer’s disease treatment (0.696) |
121 | Apoptosis agonist (0.888) Anti-neoplastic (0.860) |
Anti-eczematic (0.910) Cytostatic (0.643) |
122 | Neurodegenerative diseases treatment (0.913) Alzheimer’s disease treatment (0.889) |
Anti-eczematic (0.926) Anti-Parkinsonian (0.856) |
123 | Lipoprotein disorders treatment (0.968) Anti-diabetic (0.953) |
Anti-eczematic (0.912) Alzheimer’s disease treatment (0.670) |
124 | Anti-eczematic (0.930) Myocardial infarction treatment (0.872) |
Anti-neoplastic (0.866) Cytostatic (0.819) |
125 | Anti-eczematic (0.823) Allergic conjunctivitis treatment (0.629) |
Anti-neoplastic (0.785) Anti-inflammatory (0.731) |
126 | Myocardial infarction treatment (0.825) Anti-neoplastic (0.707) |
Anti-eczematic (0.815) Allergic conjunctivitis treatment (0.618) |
127 | Anti-neoplastic (0.918) Apoptosis agonist (0.793) Anti-neoplastic (myeloid leukemia) (0.520) |
Respiratory analeptic (0.757) Anti-secretoric (0.755) Lipid metabolism regulator (0.677) |
128 | Anti-neoplastic (0.892) Apoptosis agonist (0.796) Anti-metastatic (0.551) |
Hepatoprotectant (0.739) Hepatic disorders treatment (0.701) Dermatologic (0.614) |
129 | Cytostatic (0.863) Anti-neoplastic (0.826) Apoptosis agonist (0.797) |
Anti-eczematic (0.929) Macular degeneration treatment (0.856) Alzheimer’s disease treatment (0.729) |
130 | Lipoprotein disorders treatment (0.952) Anti-diabetic (0.943) Anti-asthmatic (0.593) |
Anti-eczematic (0.904) Anti-neoplastic (0.765) Anti-leukemic (0.651) |
131 | Insulin promoter (0.986) Myocardial infarction treatment (0.868) Anti-neoplastic (0.833) Apoptosis agonist (0.768) |
Anti-eczematic (0.910) Anti-fungal (0.670) Anti-psoriatic (0.582) Anti-bacterial (0.535) |
132 | Anti-eczematic (0.914) Anti-fungal (0.795) Anti-parasitic (0.756) |
Anti-neoplastic (0.854) Apoptosis agonist (0.786) Cytostatic (0.722) |
133 | Anti-neoplastic (0.914) Apoptosis agonist (0.823) |
Anti-asthmatic (0.834) Anti-allergic (0.828) |
* Only activities with Pa > 0.7 are shown.
Jaborochlorodiol (125) and jaborochlorotriol (126), representing a new structural type of chlorinated steroid, were identified in extracts from Jaborosa magellanica, a flowering plant of the Solanaceae family found in Punta Arenas, Chile [166]. Furthermore, the aerial parts of Tolpis proustii and T. lagopoda, native to La Gomera, Canary Islands, led to the isolation of chlorinated sterols: 30-chloro-3β-acetoxy-22α-hydroxyl-20(21)-taraxastene (127) and its acetylated analogue (128). In vitro antioxidant activities of the extracts were evaluated using the DPPH and ABTS scavenging methods. The cytotoxicity of isolated compounds demonstrated activity against the human myeloid leukemia K-562 and K-562/ADR cell lines [167].
Withanolide Z (129) was isolated from Withania somnifera as an inhibitor of topoisomerase I from the parasite Leishmania donovani, suggesting its potential in anti-parasitic applications [168]. Cytotoxic phyperunolides C (130) were found in the leaves of Physalis peruviana [169,170], highlighting their potential cytotoxic properties. Hsieh et al. [171] isolated cytotoxic tubocapsenolide G (131) from Tubocapsicum anomalum.
Physagulin I (132, the 3D graph is shown in Figure 27), a 14β-hydroxywithanolide, has been isolated from Physalis species and possesses an α-oxygenated functionality at position 15 [172]. Additionally, jaborosalactol 23 (133), another 14β-hydroxywithanolide, has been identified in Jaborosa bergii, a flowering plant in the Solanaceae family [173]. Nicotra et al. [174] reported the isomeric chlorohydrin, jaborosalactone 37 (134, structure seen in Figure 28, and activity see in Table 7), from Jaborosa rotacea, and jaborosalactone T (135) was isolated from Jaborosa sativa (synonym Trechonaetes sativa) collected in Argentina [175]. Anomanolide D (136), identified as the 16α-hydroxy substituent, was discovered in the fruits of Tubocapsicum anomalum collected in Japan [176]. Additionally, tubonolide A (137, the 3D graph is shown in Figure 29), a 16,17-dihydroxylated withajardin, was found in the same plant [177].
Table 7.
No. | Dominated Biological Activity (Pa) * | Additional Predicted Activities (Pa) * |
---|---|---|
134 | Apoptosis agonist (0.806) Anti-neoplastic (0.803) |
Genital warts treatment (0.724) Anti-eczematic (0.718) |
135 | Insulin promoter (0.981) Myocardial infarction treatment (0.819) |
Anti-neoplastic (0.797) Apoptosis agonist (0.695) |
136 | Insulin promoter (0.986) Myocardial infarction treatment (0.899) |
Anti-neoplastic (0.866) Apoptosis agonist (0.772) |
137 | Insulin promoter (0.986) Myocardial infarction treatment (0.899) |
Anti-neoplastic (0.839) Apoptosis agonist (0.696) |
138 | Anti-neoplastic (0.875) Apoptosis agonist (0.795) |
Anti-asthmatic (0.816) Anti-allergic (0.533) |
139 | Anti-neoplastic (0.885) Apoptosis agonist (0.824) |
Anti-psoriatic (0.595) Anti-allergic (0.539) |
140 | Anti-neoplastic (0.806) Apoptosis agonist (0.634) |
Myocardial infarction treatment (0.781) Hypolipemic (0.599) |
141 | Hepatic disorders treatment (0.934) Immunosuppressant (0.691) |
Anti-allergic (0.618) Allergic conjunctivitis treatment (0.543) |
142 | Hepatic disorders treatment (0.942) Anti-neoplastic (0.782) |
Anti-allergic (0.758) Anti-asthmatic (0.728) |
143 | Hepatic disorders treatment (0.930) Anti-neoplastic (0.753) |
Anti-allergic (0.711) Allergic conjunctivitis treatment (0.597) |
144 | Anti-neoplastic (0.888) Apoptosis agonist (0.761) |
Anti-inflammatory (0.815) Anti-fungal (0.629) |
145 | Anti-neoplastic (0.907) Apoptosis agonist (0.673) |
Anti-inflammatory (0.824) Anti-fungal (0.597) |
146 | Anti-eczematic (0.850) Anti-neoplastic (0.765) |
Allergic conjunctivitis treatment (0.649) Anti-allergic (0.641) |
147 | Anti-eczematic (0.850) Anti-pruritic (0.787) |
Allergic conjunctivitis treatment (0.649) Anti-allergic (0.641) |
148 | Anti-protozoal (0.956) Genital warts treatment (0.824) |
Anti-neoplastic (0.761) Anti-metastatic (0.530) |
149 | Anti-protozoal (0.954) Genital warts treatment (0.805) |
Anti-neoplastic (0.759) Apoptosis agonist (0.540) |
150 | Anti-protozoal (0.958) Anti-protozoal (Plasmodium) (0.953) |
Genital warts treatment (0.798) Anti-neoplastic (0.766) |
151 | Insulin promoter (0.984) Cytostatic (0.907) |
Anti-eczematic (0.907) Anti-fungal (0.752) |
152 | Insulin promoter (0.982) Cytostatic (0.921) |
Anti-eczematic (0.919) Macular degeneration treatment (0.912) |
153 | Anti-eczematic (0.922) Macular degeneration treatment (0.913) |
Anti-neoplastic (0.868) Cytostatic (0.866) |
* Only activities with Pa > 0.7 are shown.
Unusual 15,21-cyclowithanolides of the norbornane type, jaborosalactols 21 (138) and 22 (139), were isolated from Jaborosa bergii [178]. Furthermore, the acid hydrolysate of a methanolic extract of Tubocapsicum anomalum contained TH-6 (140) [179]. These discoveries highlight the occurrence of chlorine-containing steroids in plants, particularly in the Solanaceae family. The identification and characterization of these compounds contribute to our understanding of the chemical diversity of natural products and their potential biological activities. Further research is needed to explore the mechanisms of action and therapeutic applications of these chlorine-containing steroids in various fields, including medicine and agriculture.
A group of spiranoid withanolides with a 17(20)-ene-22-keto system, namely jaborosalactones 3 (142) and 6 (143), were isolated from Jaborosa runcinata collected in Argentina [180]. These compounds represent chlorinated steroids with unique structural features. Additionally, jaborosalactone 10 (141), presented in a 3D graph in Figure 30, was found in both J. runcinata and J. odonelliana [181]. This compound further expands our understanding of the chemical diversity within the Jaborosa genus.
Two chlorinated 24,25-epoxy-γ-lactols (144 and 145) were isolated from plants of Jaborosa parviflora [182]. These compounds possess a chlorine atom and an epoxy group within their structures, contributing to their distinctive properties. Furthermore, the chlorohydrins jaborosalactone 42 (146) and jaborosalactone 49 (147) were detected in Jaborosa caulescens var. bipinnatifida [183] and Jaborosa laciniata [184]. These compounds exhibit a chlorohydrin moiety, further enhancing the chemical diversity within the Jaborosa species.
A group of constituents called physalins, which belong to the 13,14-seco-16,24-cycloergostane class of compounds, have been identified in extracts of Brachistus stramoniifolius, Margaranthus solanaceous (sub nom. Physalis solanaceous), and Schraderanthus viscosus (sub nom. Saracha viscosa) [185,186,187]. These compounds, including physalins 148, 149, 150, and 151 (the 3D graph is shown in Figure 31), exhibit unique structural characteristics within the 13,14-seco-16,24-cycloergostane framework.
Two withanolides with a hemiketal bridge between what was originally ketone functions at C-12 and C-22 have also been discovered. Upon formation of the D-lactone, these compounds, known as 152 and 153, were detected and identified from Jaborosa rotacea [188]. These compounds demonstrate a distinct structural arrangement, featuring a six-membered ring with a β-oriented hydroxy group at C-12 and a spiroketal at C-22. Figure 28 and Figure 32 showcase the structures of various steroids, providing an overview of the diversity within the class. Furthermore, Table 1 presents the biological activities associated with plant chlorinated steroids, highlighting their cytostatic, anti-neoplastic, anti-eczematic, anti-diabetic, anti-bacterial, and other activities. These chlorinated steroids exhibit a range of characteristic biological activities, indicating their potential significance in various fields, including medicine, pharmacology, and agriculture. However, it is important to conduct further research, including in vitro and in vivo studies, to fully understand the mechanisms of action, therapeutic potential, and safety profile of these compounds.
4.2. Halogenated Steroids Derived from Marine Sources
Halogenated steroids derived from marine sources are natural compounds that contain halogen atoms (such as chlorine, bromine, or iodine) and are obtained from various marine organisms. These marine organisms can include algae, sponges, corals, mollusks, and other marine invertebrates. Halogenated steroids from marine sources exhibit diverse chemical structures and biological activities, making them of interest in the fields of pharmacology and drug discovery [143,145,147,154].
Strong cytotoxic chlorinated steroids known as clionastatins A (154) and B (155) have been discovered in the burrowing sponge Cliona nigricans. The structures of marine steroids can be observed in Figure 32 and activity see in Table 8. These remarkable compounds contain tri- and tetrachlorinated androstane derivatives, respectively. They are considered the first polyhalogenated steroids found in a living organism, whether marine or terrestrial, and represent the first instances of halogenated androstanes in nature [189]. Clionastatins A and B exhibit potent cytotoxic activity, making them of significant interest in the field of cancer research and drug development. These compounds have shown the ability to inhibit the growth of cancer cells in vitro and have demonstrated promising anti-cancer potential.
Table 8.
No. | Dominated Biological Activity (Pa) * | Additional Predicted Activities (Pa) * |
---|---|---|
154 | Anti-neoplastic (0.860) Prostate disorders treatment (0.781) |
Bone diseases treatment (0.722) Anti-inflammatory (0.639) |
155 | Anti-neoplastic (0.894) Prostate disorders treatment (0.799) |
Bone diseases treatment (0.787) Anti-inflammatory (0.731) |
156 | Anti-neoplastic (0.934) Prostate cancer treatment (0.885) Anti-neoplastic (sarcoma) (0.875) Anti-neoplastic (renal cancer) (0.820) |
Choleretic (0.879) Anti-hypercholesterolemic (0.828) Anti-fungal (0.781) Dermatologic (0.778) |
157 | Anti-neoplastic (0.922) Anti-neoplastic (sarcoma) (0.836) |
Anti-osteoporotic (0.803) Bone diseases treatment (0.781) |
158 | Anti-hypercholesterolemic (0.937) Atherosclerosis treatment (0.831) |
Respiratory analeptic (0.878) Anti-infertility, female (0.833) |
159 | Anti-neoplastic (0.881) Growth stimulant (0.751) |
Dermatologic (0.771) Anti-fungal (0.696) |
160 | Anti-hypercholesterolemic (0.885) | Anesthetic general (0.823) |
161 | Anti-neoplastic (0.810) Apoptosis agonist (0.776) |
Prostate disorders treatment (0.688) Acute neurologic disorders treatment (0.680) |
162 | Anti-neoplastic (0.805) Apoptosis agonist (0.744) Cytoprotectant (0.690) Prostate disorders treatment (0.681) |
Dermatologic (0.750) Anti-viral (influenza) (0.738) Anti-bacterial (0.736) Anti-fungal (0.728) |
163 | Anti-neoplastic (0.805) Apoptosis agonist (0.744) Cytoprotectant (0.690) Prostate disorders treatment (0.681) |
Dermatologic (0.750) Anti-viral (influenza) (0.738) Anti-bacterial (0.736) Anti-fungal (0.728) |
164 | Anti-neoplastic (0.851) Anti-carcinogenic (0.754) |
Biliary tract disorders treatment (0.841) Bone diseases treatment (0.725) |
165 | Anti-neoplastic (0.882) Cytostatic (0.793) |
Anti-bacterial (0.736) Anti-fungal (0.695) |
166 | Anti-neoplastic (0.822) Cytostatic (0.782) |
Anti-parasitic (0.718) Anti-protozoal (0.714) |
167 | Glucan endo-1,3-b-D-glucosidase inhibitor (0.890) | Biliary tract disorders treatment (0.845) |
168 | Anti-neoplastic (0.884) | Anti-inflammatory (0.829) |
169 | Anti-inflammatory (0.829) Anti-viral (0.826) |
Anti-neoplastic (0.784) Apoptosis agonist (0.763) |
170 | Anti-hypercholesterolemic (0.941) Atherosclerosis treatment (0.831) |
Anti-infertility, female (0.833) Prostate disorders treatment (0.773) |
171 | Anti-neoplastic (0.912) Cytoprotectant (0.764) Prostate disorders treatment (0.767) |
Respiratory analeptic (0.894) Erythropoiesis stimulant (0.776) |
172 | Anti-neoplastic (0.912) Cytoprotectant (0.764) Prostate disorders treatment (0.767) |
Respiratory analeptic (0.894) Erythropoiesis stimulant (0.776) Apoptosis agonist (0.677) |
173 | Anti-hypercholesterolemic (0.911) Myocardial infarction treatment (0.900) Atherosclerosis treatment (0.811) |
Apoptosis agonist (0.862) Anti-neoplastic (0.846) Prostate disorders treatment (0.823) |
174 | Respiratory analeptic (0.911) Myocardial infarction treatment (0.906) |
Anti-hypercholesterolemic (0.845) Anti-diabetic (type 2) (0.669) |
175 | Myocardial infarction treatment (0.864) Immunosuppressant (0.734) |
Dermatologic (0.785) Anti-psoriatic (0.728) |
* Only activities with Pa > 0.7 are shown.
The discovery of clionastatins A and B highlights the unique chemistry and biodiversity found in marine organisms. These compounds contribute to our understanding of the natural products derived from marine sources and their potential therapeutic applications. Further research is needed to elucidate the precise mechanisms of action and therapeutic potential of clionastatins A and B, as well as to explore their structure–activity relationships. Investigating these compounds can provide insights into the development of novel anti-cancer agents and inspire the discovery of additional halogenated steroids derived from marine organisms.
Aragusterol C (156), a chlorinated steroid, was isolated from an Okinawan marine sponge of the genus Xestospongia sp. This compound exhibited strong inhibitory effects on the proliferation of KB cells in vitro. Furthermore, it demonstrated potent in vivo anti-tumor activity against L1210 cells in mice [190]. The distribution of biological activity percentages for aragusterol C is depicted in Figure 33. Another compound, aragusteroketal C (157), which is a steroid with a dimethylketal structure, was also isolated from the same sponge. This chlorinated steroid displayed cytotoxic activity against the KB tumor cell line, with an IC50 value of 4 ng/mL [191]. Additionally, a chlorinated steroid (158) was isolated from the soft coral Sinularia brassica. This coral-derived compound offers unique structural and chemical characteristics [192]. The coral sample associated with this compound is shown in Figure 34.
Cytotoxic chlorinated ketosteroids known as kiheisterones C (159), D (160), and E (161) were discovered in the extracts of the marine sponge Strongylacedon sp. from Maui [193]. These compounds exhibit cytotoxic activity and represent an intriguing class of chlorinated ketosteroids derived from a marine source. In addition, unique pentacyclic saturated sesterpenes condensed with a hydroxy-hydroquinone moiety, known as 6′-chlorodisidein (162) and 6′-bromodisidein (163), have been isolated from the marine sponge Disidea pallescens in the form of disulfate sodium calcium salts [194]. These compounds possess a distinct structural arrangement, incorporating both chlorine and bromine atoms. The discovery of these chlorinated compounds further highlights the chemical diversity and pharmacological potential of natural products derived from marine organisms. The cytotoxic and unique structural characteristics of kiheisterones and disideins offer promising avenues for further exploration in the fields of cancer research and drug development.
Chalinulasterol (164), a chlorinated sterol disulfate, was isolated from the Caribbean sponge Chalinula molitba [195]. This compound represents a unique chlorinated sterol derivative found in a marine organism. Nakiterpiosinone (165) and nakiterpiosin (166), two related C-nor-D homosteroids, were identified in MeOH extracts of the sponge Terpios hoshinota. These compounds have shown potential as anti-cancer agents, particularly in tumors resistant to existing anti-mitotic agents and dependent on Hedgehog pathway responses for growth [196,197]. Their discovery highlights the importance of exploring marine sources for novel compounds with therapeutic potential.
The marine sponge Topsentia sp. yielded a chlorine-containing steroid sulfate (167) and the first natural iodinated steroid (168) [198]. These compounds showcase the chemical diversity of halogenated steroids derived from marine sources and contribute to our understanding of the unique natural products found in marine organisms. Chlorinated stypotriol triacetate (169) was detected in the dichloromethane extract of the brown alga Stypopodium flabelliforme [199]. This compound represents a chlorinated derivative of stypotriol, a sterol commonly found in brown algae. The identification of chlorinated derivatives expands our knowledge of the chemical variations within marine sterols. Furthermore, the (3β,5α,22R,23S)-22-chlorocholesta-8,14-diene-3,23-diol (170) was found in MeOH-CHCl3 extracts of the starfish Echinaster sepositus [200]. This chlorinated steroid exhibits a unique structural arrangement and represents an interesting discovery in the field of marine natural products.
Two unique chloro-pregnane steroids (171 and 172) have been isolated from the eastern Pacific octocoral Carijoa multiflora [201]. These compounds exhibit distinct structures and represent novel chlorinated steroids found in the marine environment. The 3D graph depicting the predicted and calculated activity for compound 171 is shown in Figure 35. In addition, three chlorinated steroids, namely yonarasterols G (173), H (174), and I (175), were discovered in MeOH extracts of the Okinawan soft coral Clavularia viridis [202]. These compounds contribute to the growing repertoire of chlorinated steroids derived from marine sources. These compounds exhibit diverse chemical architectures and display unique halogenation patterns that contribute to their biological activities. The biological activities of marine halogenated steroids are varied, with anti-tumor, anti-fungal, anti-cancer, and anti-bacterial activities being characteristic among the compounds. Particularly, anti-cancer activity appears to be a common feature observed in the presented steroids.
5. Conclusions
This comprehensive review has explored the diverse range of biological activity and structural variations found within steroids and related isoprenoid lipids. The analysis encompassed various natural compounds, including steroids with aromatic ring(s), steroid phosphate esters from marine invertebrates, and steroids bearing halogen atoms (I, Br, or Cl). These compounds are derived from sources such as fungi, fungal endophytes, plants, algae, and marine invertebrates. Through an examination of referenced literature sources, their biological activity was evaluated through in vivo and in vitro studies, as well as employing the QSAR method. The findings revealed a multitude of compounds exhibiting remarkable properties, including strong anti-neoplastic, anti-proliferative, anti-hypercholesterolemic, anti-Parkinsonian, anti-eczematic, anti-psoriatic, and various other activities. To enhance comprehension, the review incorporated visual aids such as 3D graphs illustrating the activity of individual steroids and images showcasing selected terrestrial or marine organisms. Furthermore, the review provided explanations elucidating certain types of biological activity associated with these compounds. Overall, the findings presented in this review not only contribute to the academic scientific knowledge in the field but also hold practical relevance for the development of pharmacological interventions and advancements in practical medicine. The review utilized data from various authors regarding the biological activity of natural steroids. To assess the potential activity of these steroids, the PASS program was employed. The PASS program utilizes structural features of compounds to predict their biological activity profiles. By inputting the structural information of the natural steroids into the program, their potential activity across multiple predefined activity classes was estimated. However, it is important to note that these predictions are based solely on structural information and should be validated through experimental studies.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The author declares that he has no known competing financial interests or personal relationships that could affect the work described in this article.
Funding Statement
This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Footnotes
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