Steroid phosphate esters and phosphonosteroids and

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Jul 11, 2018 - Abstract. Steroid phosphate esters are very rare natural lipids that have been comparatively recently isolated from fractions of polar lipids of.

Steroid phosphate esters and phosphonosteroids and their biological activities Valery M. Dembitsky, Tatyana A. Gloriozova & Nick Savidov

Applied Microbiology and Biotechnology ISSN 0175-7598 Volume 102 Number 18 Appl Microbiol Biotechnol (2018) 102:7679-7692 DOI 10.1007/s00253-018-9206-z

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Author's personal copy Applied Microbiology and Biotechnology (2018) 102:7679–7692 https://doi.org/10.1007/s00253-018-9206-z

MINI-REVIEW

Steroid phosphate esters and phosphonosteroids and their biological activities Valery M. Dembitsky 1,2 & Tatyana A. Gloriozova 3 & Nick Savidov 1 Received: 22 March 2018 / Revised: 27 June 2018 / Accepted: 27 June 2018 / Published online: 11 July 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract Steroid phosphate esters are very rare natural lipids that have been comparatively recently isolated from fractions of polar lipids of marine sponges and starfish. These steroids exhibit interesting biological activities. When using the PASS computer program, we showed that many of steroid phosphate esters showed antifungal, antihypercholesterolemic, anesthetic, and other activities with a confidence of 73 to 93%. In addition, some of them can be used as inhibitors of cholesterol synthesis and show hepatoprotection properties. Phosphonosteroids demonstrate antineoplastic and antihypercholesterolemic activities with a certainty of 85 to 90%. And also, they can be used as ovulation inhibitors or female steroid contraceptives with confidence from 86 to 98%. Keywords Steroids . Lipids . Marine sponges . Starfish . Steroid phosphate esters . Phosphonosteroids

Introduction Phosphorus (atomic number 15) is one of the most spread chemical elements in the earth’s crust and sea water (Turekian and Wedepohl 1961; Dhuime et al. 2015; Worsfold et al. 2016). About 350 years ago, the German physicist Hennig Brand first discovered phosphorus in 1669 (Krafft 1969). Free phosphorus has a large reactive activity, so in nature, as a rule, it occurs in the form of salts of phosphoric acid—phosphates (Holmes 1996). The most important mineral compound of phosphorus is apatite (Su et al. 2017; Dorozhkin 2011). Phosphorus is a part of the most important molecular structures such as biological membranes. So, phosphorus is one of the important structural elements of DNA and RNA. Both these genetic molecules have a sugar-phosphate backbone. Phosphate works as a Bsuper glue,^ since it has three oxygen atoms, which carry the charge in solution (Dorozhkin 2008, 2010). Given that biological membranes form lipid molecules, in particular polar

* Valery M. Dembitsky [email protected] 1

Centre for Applied Research and Innovation, Lethbridge College, 3000 College Drive South, Lethbridge, AB T1K 1L6, Canada

2

Biochemical Lab, National Scientific Center of Marine Biology, 17 Palchevsky Str., Vladivostok, Russia 690041

3

Institute of Biomedical Chemistry, Moscow, Russia 119121

phospholipids, the biological role of phosphorus is therefore indispensable (Yeagle 2016; Dorozhkin and Epple 2002). Relationships between chemical structure and biological activity have been known for over 150 years (Barlow 1979). This principle is widely used in pharmacology, biochemistry, bioorganic chemistry, and medicine. There are different approaches and methods, but the relationships between structure and activity are constantly preserved. One of the existing methods is the computer program PASS, which contains about one million chemical compounds and more than 8800 biological activities. In a number of publications, this method was used and it proved to be very practical with a large degree of effectiveness (Dembitsky and Gloriozova 2017; Dembitsky et al. 2017a, b, c; Levitsky et al. 2017). The algorithm of PASS practical utilization is described in detail in several publications (Filz and Poroikov 2012; Levitsky et al. 2016; Sergeiko et al. 2008; Gloriozova et al. 2017). It is known that steroids are also structural molecules of biological membranes. However, steroids phosphate esters have been discovered quite recently. This mini review is devoted to steroid phosphate esters and phosphonosteroids and their biological activity.

Steroid phosphate esters For the first time, steroids phosphates were discovered more than a quarter of a century ago by Italian scientists from the

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Fig. 1 Natural bioactive steroid phosphate esters

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Author's personal copy Appl Microbiol Biotechnol (2018) 102:7679–7692 Table 1

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Predicted biological activities of steroid phosphate esters

No. Predicted biological activities of steroids phosphates (Pa)* 1

2

Wound healing agent (0.975); hepatoprotectant (0.961); analeptic (0.952); laxative (0.933); antihypercholesterolemic (0.926); anticarcinogenic (0.912); hemostatic (0.853); antineoplastic (0.841); antibacterial (0.840); antifungal (0.823); cholesterol synthesis inhibitor (0.799); biliary tract disorders treatment (0.791); neuroprotector (0.758); antiinflammatory (0.726); acute neurologic disorders treatment (0.717); anesthetic general (0.696); proliferative diseases treatment (0.641) Hepatoprotectant (0.874); analeptic (0.874); anticarcinogenic (0.861); antineoplastic (0.848); antibacterial (0.826); antifungal (0.815); antihypercholesterolemic (0.789); cholesterol synthesis inhibitor (0.751); biliary tract disorders treatment (0.735); antiinflammatory (0.730); Wound healing agent (0.654); proliferative diseases treatment (0.556); atherosclerosis treatment (0.518); laxative (0.506); neuroprotector (0.506)

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Wound healing agent (0.947); analeptic (0.941); hepatoprotectant (0.932); anticarcinogenic (0.915); antihypercholesterolemic (0.912); laxative (0.852); antineoplastic (0.843); antibacterial (0.835); antifungal (0.827); cholesterol synthesis inhibitor (0.778); biliary tract disorders treatment (0.767); neuroprotector (0.755); antiinflammatory (0.737); acute neurologic disorders treatment (0.677); proliferative diseases treatment (0.645)

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Antihypercholesterolemic (0.894); hepatoprotectant (0.853); wound healing agent (0.844); antineoplastic (0.816); antiinflammatory (0.782); cholesterol synthesis inhibitor (0.778); biliary tract disorders treatment (0.734); antifungal (0.732); anticarcinogenic (0.700); hemostatic (0.698); atherosclerosis treatment (0.675); antieczematic (0.641); antipsoriatic (0.621); antibacterial (0.594); analeptic (0.565); antiosteoporotic (0.556) Antifungal (0.822); antineoplastic (0.816); antiinflammatory (0.715); antibacterial (0.670); cholesterol synthesis inhibitor (0.618)

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Anticarcinogenic (0.607); dermatologic (0.607); hepatic disorders treatment (0.587); biliary tract disorders treatment (0.547) Antineoplastic (0.845); antifungal (0.814); antiinflammatory (0.693); antibacterial (0.651); dermatologic (0.597); cholesterol synthesis inhibitor (0.586); anticarcinogenic (0.571); hepatic disorders treatment (0.543)

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Antifungal (0.837); antineoplastic (0.824); antiinflammatory (0.738); antibacterial (0.695); dermatologic (0.592); cholesterol synthesis inhibitor (0.572); hepatic disorders treatment (0.538); antineoplastic (renal cancer) (0.527); chemoprotective (0.508); anticarcinogenic (0.505)

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Antineoplastic (0.827); antifungal (0.663); immunosuppressant (0.644); antibacterial (0.636); antineoplastic (liver cancer) (0.607) Antiinflammatory (0.562); dermatologic (0.550); hepatic disorders treatment (0.545); chemopreventive (0.506) Antineoplastic (0.852); antineoplastic (liver cancer) (0.790); antieczematic (0.730); antiallergic (0.650); immunosuppressant (0.617); antifungal (0.605); antiasthmatic (0.581); genital warts treatment (0.571); antibacterial (0.563); antiinflammatory (0.527); antileukemic (0.504) Antineoplastic (0.852); antineoplastic (liver cancer) (0.790); antieczematic (0.730); antiallergic (0.650); immunosuppressant (0.617); antifungal (0.605); antiasthmatic (0.581); genital warts treatment (0.571); antibacterial (0.563); antiinflammatory (0.527); antileukemic (0.504) Antineoplastic (0.827); antifungal (0.663); immunosuppressant (0.644); antibacterial (0.636); antineoplastic (liver cancer) (0.607) Antiinflammatory (0.562); dermatologic (0.550); hepatic disorders treatment (0.545); chemopreventive (0.506) Antineoplastic (0.841); anesthetic general (0.826); antifungal (0.799); immunosuppressant (0.791); neuroprotector (0.784); antiinflammatory (0.713); antiviral (Influenza) (0.709); antieczematic (0.705); respiratory analeptic (0.623); apoptosis agonist (0.615); antibacterial (0.607); antipsoriatic (0.580); cholesterol synthesis inhibitor (0.554); antiparasitic (0.552); hypolipemic (0.533); prostate disorders treatment (0.509) Antifungal (0.850); antineoplastic (0.832); antibacterial (0.717); antiinflammatory (0.717); anticarcinogenic (0.707); chemopreventive (0.703); cholesterol synthesis inhibitor (0.646); hepatoprotectant (0.613); biliary tract disorders treatment (0.542); laxative (0.531); antipsoriatic (0.526)

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Antifungal (0.850); antineoplastic (0.832); antibacterial (0.717); antiinflammatory (0.717); anticarcinogenic (0.707); chemopreventive (0.703)

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Cholesterol synthesis inhibitor (0.646); hepatoprotectant (0.613); biliary tract disorders treatment (0.542); laxative (0.531); antipsoriatic (0.526) Antifungal (0.841); antineoplastic (0.832); antibacterial (0.738); chemopreventive (0.676); antiinflammatory (0.603); apoptosis agonist (0.564)

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17

18

19

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Anticarcinogenic (0.547); antimetastatic (0.540); hepatic disorders treatment (0.524); cholesterol synthesis inhibitor (0.520); dermatologic (0.519) Antiinflammatory (0.910); anesthetic general (0.908); respiratory analeptic (0.904); antiosteoporotic (0.878); antiseborrheic (0.822) Antineoplastic (0.793); antipruritic (0.788); immunosuppressant (0.757); antiallergic (0.756); prostate disorders treatment (0.680) Rheumatoid arthritis treatment (0.612); apoptosis agonist (0.591); erythropoiesis stimulant (0.578); ovulation inhibitor (0.561) Proliferative diseases treatment (0.560); menopausal disorders treatment (0.538) Neuroprotector (0.987); anesthetic general (0.959); respiratory analeptic (0.944); antihypercholesterolemic (0.909); antineoplastic (0.859) Radioprotector (0.803); acute neurologic disorders treatment (0.779); antiinflammatory (0.735); vasoprotector (0.728); ovulation inhibitor (0.724) Antiosteoporotic (0.715); antipruritic (0.698); menopausal disorders treatment (0.690); psychostimulant (0.661); prostate cancer treatment (0.652) Anesthetic general (0.991); respiratory analeptic (0.990); neuroprotector (0.976); antiinflammatory (0.906); antihypercholesterolemic (0.894) Antineoplastic (0.818); antipruritic (0.811); proliferative diseases treatment (0.766); antiallergic (0.730); prostate disorders treatment (0.706) Acute neurologic disorders treatment (0.669); menopausal disorders treatment (0.648); anticarcinogenic (0.641); antiosteoporotic (0.633) Respiratory analeptic (0.979); anesthetic general (0.973); neuroprotector (0.972); antihypercholesterolemic (0.971); wound healing agent (0.913) Antineoplastic (0.826); cholesterol synthesis inhibitor (0.801); radioprotector (0.793); antieczematic (0.783); antiprotozoal (Leishmania) (0.781) Antipruritic (0.776); proliferative diseases treatment (0.768); antiosteoporotic (0.738); antiinflammatory (0.721); anticarcinogenic (0.709) Prostate disorders treatment (0.699); antipsoriatic (0.695) Respiratory analeptic (0.995); anesthetic general (0.948); antihypercholesterolemic (0.945); neuroprotector (0.932); hemostatic (0.910) Wound healing agent (0.897); cholesterol synthesis inhibitor (0.867); acute neurologic disorders treatment (0.827); antineoplastic (0.817)

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Table 1 (continued) No. Predicted biological activities of steroids phosphates (Pa)* Anticarcinogenic (0.803); vasoprotector (0.788); radioprotector (0.782); antieczematic (0.766); lipoprotein disorders treatment (0.728) Antifungal (0.714); antiinflammatory (0.680); antiosteoporotic (0.651); prostate disorders treatment (0.581) 21

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Respiratory analeptic (0.995); antihypercholesterolemic (0.967); anesthetic general (0.954); hemostatic (0.928); wound healing agent (0.921) Neuroprotector (0.909); chemopreventive (0.876); cholesterol synthesis inhibitor (0.872); antineoplastic (0.825); anticarcinogenic (0.810) Radioprotector (0.797); acute neurologic disorders treatment (0.796); vasoprotector (0.769); antieczematic (0.763); lipoprotein disorders treatment (0.751); antiinflammatory (0.715); antifungal (0.699); antiosteoporotic (0.655); prostate disorders treatment (0.577); laxative (0.570) Antihypercholesterolemic (0.996); cholesterol absorption inhibitor (0.976); cholesterol synthesis inhibitor (0.952); lipid metabolism regulator (0.952) Acute neurologic disorders treatment (0.948); antihyperlipoproteinemic (0.920); hypolipemic (0.919); respiratory analeptic (0.908) Antifungal (0.893); lipoprotein disorders treatment (0.893); immunosuppressant (0.873); antieczematic (0.811); antineoplastic (0.800) Neuroprotector (0.720); antibacterial (0.700); apoptosis agonist (0.659); antipsoriatic (0.656); atherosclerosis treatment (0.608)

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Antihypercholesterolemic (0.999); antihyperlipoproteinemic (0.986); hypolipemic (0.974); cholesterol absorption inhibitor (0.957) Lipid metabolism regulator (0.954); cholesterol synthesis inhibitor (0.916); antifungal (0.880); immunosuppressant (0.828); antieczematic (0.814) Antineoplastic (0.810); lipoprotein disorders treatment (0.782); acute neurologic disorders treatment (0.751); atherosclerosis treatment (0.729) Antipsoriatic (0.697); antibacterial (0.664); apoptosis agonist (0.663); respiratory analeptic (0.571); anesthetic (0.568); antileukemic (0.565)

*Only activities with Pa > 0.5 are shown

University of Frederico II, the city of Napoli. Steroids were isolated from the extract of the polar lipids of the starfish Tremaster novaecaledoniae, which was collected at a depth of 530 m of New Caledonia (De Riccardis et al. 1993). The isolated phosphated steroid glycosides were called tremasterols А-C, and their structures were identified as 3βO-sulphated, 6α-O-phosphated, and 16β-O-acetylated groupings on a steroidal skeleton (1–4, structures are shown in Fig. 1, the activities are shown in Table 1). Two phosphorylated sterol sulfates as MT1-MMP inhibitors called haplosamates A (5), B (6) and minor secosteroid (7) were from a marine sponge Cribrochalina sp. (Fujita et al. 2001). The isolated steroids were called haplosamate A (5) and B (6). Thus, haplosamate A (5) had a unique C28 sterol containing a sulfate group at C-3 and a methyl phosphate at position 15, and haplosamate B (6) contained two phosphate group at positions 7 and 15 (Fujita et al. 2001). Other semi-synthetic analogues (8–10, 11, structures are shown in Figs. 1 and 2, the activities are shown in Table 1) have also been isolated. Desulfohaplosamate (12), haplosamate A (5), and other steroids were semi-synthetic analogues (13–15) have been evaluated for interaction with CB1 and CB2 cannabinoid receptors through a binding test. Both steroids containing a phosphate group were found in the polar organic fraction of the Indonesian sponge Dasychalina sp. extract (Chianese et al. 2011). Desulfohaplosamate (12) showed a selective affinity for CB2 receptors in the low μM range, while a semi-synthetic derivative with cleaved ring B showed a complete loss of affinity for both receptors, highlighting the importance of an intact steroid nucleus. These unique steroid phosphates are of great interest for both steroids chemistry and pharmacology.

Synthetic steroids, such as prednisone phosphate (16), testosterone 17β-phosphate (17), cortisol 21-phosphate (18), and cholesterol 3β-phosphate (19), were chosen by us for comparison from biological activity with the activity of steroids isolated from marine invertebrates. Thus, prednisone phosphate (16) has demonstrated antiinflammatory activity (Van Dullemen and Tytgat 1997). Testosterone 17β-phosphate (17) is an androgen and belongs to the class of anabolic steroids and is used for intramuscular injection, and it is a substrate for phosphatases in the phosphatase pool of the prostate (Delrio and Botte 1970). Cortisol 21phosphate (18) refers to the glucocorticoid class of hormones, and it functions to increase blood sugar levels through gluconeogenesis, and promotes the metabolism of fats, proteins, and carbohydrates. Cortisol 21-phosphate (18) is a substrate for alkaline phosphatase and is used for an enzyme immunoassay for human chorionic gonadotropin, human growth hormone, and α-fetoprotein and estradiol (Kokado et al. 1997). Cholesterol 3β-phosphate (19) promotes normalization of blood pressure and plays an important role in atherogenesis (Ellam and Chico 2012; Davis and Szoka 1998). Two novel cholesterol-lowering agents called sodium ascorbyl campestanol phosphate (20) and sodium ascorbyl sitostanol phosphate (21) were synthesized and their properties were studied (Sachs-Barrable et al. 2014). Using Western Blot analysis of P-gp expression, it was shown that changes in mdr-1 gene expression lead to correlating changes in P-gp protein expression. More recently, two steroid phosphate esters (22 and 23, structures see on Fig. 2 and activities Table 2) have been synthesized which are called inhibitors of cholesterol biosynthesis. Methods of treating or preventing various

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Fig. 2 Natural semi-synthetic and synthetic bioactive steroid phosphate esters

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Table 2

Predicted biological activities of steroid phosphate esters and phosphonosteroids

No. Predicted biological activities of steroids phosphate esters and phosphonosteroids (Pa)* 24

Antineoplastic (0.822); immunosuppressant (0.778); antiinflammatory (0.645); prostate disorders treatment (0.621); hypolipemic (0.599) Ovulation inhibitor (0.592); apoptosis agonist (0.592); menopausal disorders treatment (0.574); cytostatic (0.564); anesthetic general (0.537)

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Chemoprotective (0.509); antiosteoporotic (0.509) Neuroprotector (0.982); anesthetic general (0.931); antiseborrheic (0.930); antihypercholesterolemic (0.909); alopecia treatment (0.866) Respiratory analeptic (0.865); acute neurologic disorders treatment (0.831); antineoplastic (0.820); radioprotector (0.799); vasoprotector (0.795) Antiosteoporotic (0.752); immunosuppressant (0.732); menopausal disorders treatment (0.697); laxative (0.686); ovulation inhibitor (0.667) Prostate disorders treatment (0.640); psychostimulant (0.630)

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Anesthetic general (0.970); neuroprotector (0.965); respiratory analeptic (0.961); acute neurologic disorders treatment (0.916) Antiseborrheic (0.892); antihypercholesterolemic (0.887); alopecia treatment (0.873); age-related macular degeneration treatment (0.848) Antineoplastic (0.843); laxative (0.819); antiosteoporotic (0.788); vasoprotector (0.729); menopausal disorders treatment (0.709) Immunosuppressant (0.707); ovulation inhibitor (0.671); prostate disorders treatment (0.643)

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Antiinflammatory (0.979); antiallergic (0.959); antiasthmatic (0.951); antiarthritic (0.944); immunosuppressant (0.881); antipruritic (0.860) Proliferative diseases treatment (0.835); antineoplastic (0.787); antipsoriatic (0.765); respiratory analeptic (0.734) Inflammatory bowel disease treatment (0.651); chronic obstructive pulmonary disease treatment (0.555); prostate disorders treatment (0.552)

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Antiosteoporotic (0.509) Respiratory analeptic (0.929); antiischemic, cerebral (0.907); anesthetic general (0.897); antineoplastic (0.847); antiosteoporotic (0.807) Antipsoriatic (0.780); cardiotonic (0.774); apoptosis agonist (0.748); antiinflammatory (0.735); antihypercholesterolemic (0.695)

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30

31

32

33

34

35

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Proliferative diseases treatment (0.679); antifungal (0.678); antieczematic (0.672); chemopreventive (0.599); hepatoprotectant (0.593) Myasthenia gravis treatment (0.570); cholesterol synthesis inhibitor (0.567) Antiischemic, cerebral (0.979); respiratory analeptic (0.919); antiosteoporotic (0.843); anesthetic general (0.830); antineoplastic (0.807) Antipsoriatic (0.793); cardiotonic (0.771); antiinflammatory (0.766); proliferative diseases treatment (0.645); antifungal (0.627) Apoptosis agonist (0.579); myasthenia gravis treatment (0.572); cholesterol synthesis inhibitor (0.534) Respiratory analeptic (0.937); antiischemic, cerebral (0.922); anesthetic general (0.897); antineoplastic (0.850); antiosteoporotic (0.800) Antipsoriatic (0.779); antiinflammatory (0.781); cardiotonic (0.776); apoptosis agonist (0.760); antieczematic (0.733) Proliferative diseases treatment (0.684); antiinfertility, female (0.679); antifungal (0.677); hepatoprotectant (0.582); myasthenia gravis treatment (0.578) Antiischemic, cerebral (0.978); respiratory analeptic (0.911); antiosteoporotic (0.852); anesthetic general (0.830); antineoplastic (0.804) Antipsoriatic (0.794); cardiotonic (0.770); antiinflammatory (0.715); Proliferative diseases treatment (0.641); antifungal (0.627) Myasthenia gravis treatment (0.564); apoptosis agonist (0.562); chemopreventive (0.546); cholesterol synthesis inhibitor (0.534) Antieczematic (0.948); antineoplastic (0.894); proliferative diseases treatment (0.884); antipsoriatic (0.875); antiosteoporotic (0.825) Respiratory analeptic (0.799); antiinflammatory (0.719); antipruritic (0.716); transplant rejection treatment (0.705) Autoimmune disorders treatment (0.689); apoptosis agonist (0.683); hyperparathyroidism treatment (0.680); antimetastatic (0.606) Antileukemic (0.593) Antieczematic (0.948); antipsoriatic (0.879); antineoplastic (0.879); antiosteoporotic (0.815); proliferative diseases treatment (0.771) Autoimmune disorders treatment (0.731); hyperparathyroidism treatment (0.672); antiinflammatory (0.671); transplant rejection treatment (0.670) Apoptosis agonist (0.663); antiviral (0.619); antipruritic (0.617); antileukemic (0.598); antimetastatic (0.592); prostate cancer treatment (0.538) Antineoplastic (0.962); antieczematic (0.961); antiosteoporotic (0.951); antipsoriatic (0.930); respiratory analeptic (0.905) Antiinflammatory (0.857); proliferative diseases treatment (0.850); apoptosis agonist (0.844); radioprotector (0.823); hyperparathyroidism treatment (0.807); hypolipemic (0.778); bone formation stimulant (0.766); antidiabetic (type 1) (0.726); antipruritic (0.723); antileukemic (0.694) Autoimmune disorders treatment (0.691); transplant rejection treatment (0.681); antiacne (0.569); prostate cancer treatment (0.545) Antineoplastic (0.962); antieczematic (0.961); antiosteoporotic (0.951); antipsoriatic (0.930); respiratory analeptic (0.905) Antiinflammatory (0.857); proliferative diseases treatment (0.850); apoptosis agonist (0.844); radioprotector (0.823); hyperparathyroidism treatment (0.807); hypolipemic (0.778); bone formation stimulant (0.766); antidiabetic (type 1) (0.726); antipruritic (0.723); antileukemic (0.694) Autoimmune disorders treatment (0.691); transplant rejection treatment (0.681); antiacne (0.569); prostate cancer treatment (0.545) Respiratory analeptic (0.982); antieczematic (0.969); antiosteoporotic (0.962); antineoplastic (0.955); antipsoriatic (0.938) Hyperparathyroidism treatment (0.856); contraceptive (0.841); antiinflammatory (0.826); antipruritic (0.804); proliferative diseases treatment (0.801) Apoptosis agonist (0.777); autoimmune disorders treatment (0.753); bone formation stimulant (0.750); antidiabetic (type 1) (0.745)

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Table 2 (continued) No. Predicted biological activities of steroids phosphate esters and phosphonosteroids (Pa)* Antileukemic (0.731); psychosexual dysfunction treatment (0.724); transplant rejection treatment (0.721); hypolipemic (0.659) Antimetastatic (0.646); antiacne (0.599); prostate cancer treatment (0.592) 37

Antieczematic (0.965); respiratory analeptic (0.964); antiosteoporotic (0.947); antineoplastic (0.923); antipsoriatic (0.921) Antiinflammatory (0.837); hyperparathyroidism treatment (0.822); proliferative diseases treatment (0.815); antidiabetic (type 1) (0.800) Antipruritic (0.793); bone formation stimulant (0.764); hypolipemic (0.759); transplant rejection treatment (0.746); apoptosis agonist (0.738) Autoimmune disorders treatment (0.724); antileukemic (0.719); antimetastatic (0.648); contraceptive (0.644); prostate cancer treatment (0.509)

38

Respiratory analeptic (0.975); antieczematic (0.967); antiosteoporotic (0.964); antipsoriatic (0.951); antineoplastic (0.933); hypolipemic (0.902) Proliferative diseases treatment (0.870); apoptosis agonist (0.869); antiinflammatory (0.860); hyperparathyroidism treatment (0.828) Radioprotector (0.793); antipruritic (0.788); bone formation stimulant (0.762); antidiabetic (type 1) (0.743); contraceptive (0.730) Antileukemic (0.726); autoimmune disorders treatment (0.707); transplant rejection treatment (0.695); atherosclerosis treatment (0.684) Keratolytic (0.608); antiacne (0.607); prostate cancer treatment (0.599)

39

Antieczematic (0.964); antiosteoporotic (0.962); antineoplastic (0.940); antipsoriatic (0.939); respiratory analeptic (0.939) Apoptosis agonist (0.852); hyperparathyroidism treatment (0.844); antiinflammatory (0.842); proliferative diseases treatment (0.808) Radioprotector (0.783); antipruritic (0.780); hypolipemic (0.780); bone formation stimulant (0.771); antidiabetic (type 1) (0.747) Contraceptive (0.730); autoimmune disorders treatment (0.725); transplant rejection treatment (0.691); antileukemic (0.672); antiacne (0.587) Prostate cancer treatment (0.582)

40

Antisecretoric (0.872); antiinflammatory (0.823); antineoplastic (0.823); antiseborrheic (0.822); hypolipemic (0.789); neuroprotector (0.766) Antiarthritic (0.645); antiosteoporotic (0.617); prostate disorders treatment (0.613); bone formation stimulant (0.609); apoptosis agonist (0.602) Menopausal disorders treatment (0.592); allergic conjunctivitis treatment (0.585); anesthetic general (0.566); ovulation inhibitor (0.566)

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Stroke treatment (0.562); proliferative diseases treatment (0.527); male reproductive disfunction treatment (0.521) Neuroprotector (0.852); acute neurologic disorders treatment (0.840); hypolipemic (0.806); antisecretoric (0.795); antineoplastic (0.781) Antiseborrheic (0.764); antiosteoporotic (0.741); anesthetic general (0.691); antiinflammatory (0.651); stroke treatment (0.631)

42

Alopecia treatment (0.630); bone formation stimulant (0.610); prostate disorders treatment (0.580); menopausal disorders treatment (0.577) Anesthetic general (0.891); antiseborrheic (0.823); antineoplastic (0.804); immunosuppressant (0.760); antiinflammatory (0.703); hypolipemic (0.686); neuroprotector (0.682); antihypercholesterolemic (0.677); ovulation inhibitor (0.654); prostate disorders treatment (0.636) Antiosteoporotic (0.629); menopausal disorders treatment (0.627); respiratory analeptic (0.598); contraceptive (0.558); atherosclerosis treatment (0.552)

*Only activities with Pa > 0.5 are shown

diseases, conditions, and disorders by administering these steroids or compositions are also provided (Kutney et al. 2003). Compound (24, structures are shown in Fig. 3, the activities are shown in Table 2) is a steroid phosphate ester containing a pivalic acid. This drug was developed to deliver testosterone to the brain and is called anionic chemical delivery system (aCDS). Systemically administered T-aCDS can penetrate the brain by passive transport because of its increased lipophilicity. The tested drug showed its effectiveness (Somogyi et al. 1998). Estradiol phosphates (25 and 26) are esters of estrogen with phosphoric acid and acts as a prodrug of estradiol in the human body. In medical practice, both drugs can be used to treat prostate cancer (Gunnarsson and Norlén 1988). Betamethasone sodium phosphate (27) has been synthesized and it is used to treat asthma, allergies, arthritis, Crohn’s disease, ulcerative colitis, and adrenal disease (Zhang et al. 2017). Interesting steroid phosphate esters (28–31) were isolated from eggs of the desert locust, Schistocera gregaria. The origin of these steroids in deferred eggs is not known, but the

fact itself is interesting (Isaac et al. 1984). The biological activity of these steroids has not been studied. Recently, Sikervar and co-workers (2012) reported on the synthesis of enantiomeric 19-nor-vitamin D3 and its substituted cyclic phosphate analogues (32 and 33). However, the biological activity of the compounds obtained was not carried out.

Phosphonosteroids Phosphonolipids are lipids containing C–P covalent bond(s) that are widely distributed in nature (Hori and Nozawa 1982; Moschidis 1984; Mukhamedova and Glushenkova 2000; McGrath et al. 2013). 2-Aminoethylphosphonic acid is a part of phosphonolipids and is attached to diacylglycerol, ceramide, or to carbohydrate fragments of glycolipids. For the first time, phosphonolipids were found in rumen protozoa more 50 years ago (Horiguchi and Kandatsu 1959). Much later, they were found in protozoa, marine invertebrates, as

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Fig. 3 Bioactive synthetic steroid phosphate esters and phosphonosteroids

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Fig. 4 Bioactive synthetic phosphonosteroids

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Table 3

Predicted biological activities of phosphonosteroids

No. Predicted biological activities of phosphonosteroids (Pa)* 43

Ovulation inhibitor (0.858); antineoplastic (0.853); neuroprotector (0.837); male reproductive disfunction treatment (0.819) Prostate disorders treatment (0.726); antiseborrheic (0.723); respiratory analeptic (0.680); menopausal disorders treatment (0.635) Antiinflammatory (0.617); alopecia treatment (0.601); immunosuppressant (0.601); antiosteoporotic (0.587); endometrios treatment (0.583) Antiarthritic (0.582); prostate cancer treatment (0.578); antihypercholesterolemic (0.540); muscular dystrophy treatment (0.537)

44

Antipruritic (0.537); anesthetic general (0.530) Antiseborrheic (0.893); antineoplastic (0.790); respiratory analeptic (0.763); neuroprotector (0.755); immunosuppressant (0.734) Anesthetic general (0.722); ovulation inhibitor (0.694); antiinflammatory (0.677); menopausal disorders treatment (0.667) Prostate disorders treatment (0.658); antiosteoporotic (0.638); antihypercholesterolemic (0.606); alopecia treatment (0.602) Contraceptive (0.598); proliferative diseases treatment (0.546); antinephrotoxic (0.546)

45

Anesthetic general (0.927); antineoplastic (0.803); immunosuppressant (0.724); hypolipemic (0.699); antiseborrheic (0.698); neuroprotector (0.689) Alopecia treatment (0.672); antiosteoporotic (0.669); menopausal disorders treatment (0.644); antiinflammatory (0.636) Prostate disorders treatment (0.634); ovulation inhibitor (0.629); antihypercholesterolemic (0.599); atherosclerosis treatment (0.578)

46

Neuroprotector (0.962); anesthetic general (0.896); respiratory analeptic (0.810); antineoplastic (0.783); hypolipemic (0.761) Prostate disorders treatment (0.712); antiinflammatory (0.691); antihypercholesterolemic (0.671); menopausal disorders treatment (0.664) Anticonvulsant (0.651); antisecretoric (0.646); proliferative diseases treatment (0.616); ovulation inhibitor (0.604); antieczematic (0.599) Cholesterol synthesis inhibitor (0.545)

47

Neuroprotector (0.856); anesthetic general (0.850); hypolipemic (0.788); antineoplastic (0.785); ovulation inhibitor (0.698) Antisecretoric (0.683); antiischemic, cerebral (0.671); acute neurologic disorders treatment (0.666); antiinflammatory (0.661) Prostate disorders treatment (0.646); stroke treatment (0.639); male reproductive disfunction treatment (0.635); psychostimulant (0.606) Antiosteoporotic (0.603); menopausal disorders treatment (0.584); bone formation stimulant (0.563) Anesthetic general (0.925); respiratory analeptic (0.867); antieczematic (0.822); antiosteoporotic (0.792); antineoplastic (0.772)

48

Antihypercholesterolemic (0.762); antipruritic (0.713); bone formation stimulant (0.710); prostate disorders treatment (0.708); hypolipemic (0.682) 49

50

51

52

53

54

Antipsoriatic (0.672); antiinflammatory (0.646); neuroprotector (0.641); choleretic (0.625); antiviral (Influenza) (0.611) Anesthetic general (0.905); antieczematic (0.793); respiratory analeptic (0.775); antiosteoporotic (0.711); antihypercholesterolemic (0.677) Prostate disorders treatment (0.667); hypolipemic (0.643); bone formation stimulant (0.628); antineoplastic (0.627); antipsoriatic (0.619) Antipruritic (0.615); biliary tract disorders treatment (0.580); cholesterol synthesis inhibitor (0.563); antimetastatic (0.525) Proliferative diseases treatment (0.506) Acute neurologic disorders treatment (0.806); antiseborrheic (0.778); neuroprotector (0.753); anesthetic general (0.719); antineoplastic (0.697) Immunosuppressant (0.695); antisecretoric (0.690); bone diseases treatment (0.672); ovulation inhibitor (0.668); antiosteoporotic (0.655) Prostate disorders treatment (0.646); hypolipemic (0.626); antieczematic (0.608); menopausal disorders treatment (0.592) Atherosclerosis treatment (0.592); anticonvulsant (0.537) Anesthetic general (0.906); acute neurologic disorders treatment (0.871); antineoplastic (0.789); immunosuppressant (0.768) Respiratory analeptic (0.752); ovulation inhibitor (0.721); prostate disorders treatment (0.714); hypolipemic (0.713); antiosteoporotic (0.693) Atherosclerosis treatment (0.660); anticonvulsant (0.658); contraceptive female (0.657); antiinflammatory (0.655) Menopausal disorders treatment (0.643); antieczematic (0.625); antihypercholesterolemic (0.549) Neuroprotector (0.902); anesthetic general (0.881); acute neurologic disorders treatment (0.881); hypolipemic (0.853); antiseborrheic (0.817) Antineoplastic (0.798); antiosteoporotic (0.746); alopecia treatment (0.743); antiinflammatory (0.714); bone formation stimulant (0.653) Menopausal disorders treatment (0.648); stroke treatment (0.627); prostate disorders treatment (0.597); ovulation inhibitor (0.567) Antihypercholesterolemic (0.517) Neuroprotecto (0.991); acute neurologic disorders treatment (0.976); anticonvulsant (0.881); antiischemic, cerebral (0.872); psychostimulant (0.862) Stroke treatment (0.849); antineoplastic (0.829); antiosteoporotic (0.814); bone formation stimulant (0.747); antiseborrheic (0.736) Menopausal disorders treatment (0.724); hypolipemic (0.699); ovulation inhibitor (0.695); alopecia treatment (0.657); prostate disorders treatment (0.656); male reproductive disfunction treatment (0.642); antiepileptic (0.567) 0.965 Antiosteoporotic (0.965); antihypercholesterolemic (0.905); bone formation stimulant (0.884); anesthetic general (0.880) Menopausal disorders treatment (0.842); hypolipemic (0.834); respiratory analeptic (0.825); antieczematic (0.823); antineoplastic (0.818) Biliary tract disorders treatment (0.813); neuroprotector (0.774); antiprotozoal (0.764); antiinflammatory (0.733); apoptosis agonist (0.725) Hepatic disorders treatment (0.714); proliferative diseases treatment (0.705); antipruritic (0.705); osteoclast antagonist (0.697)

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Table 3 (continued) No. Predicted biological activities of phosphonosteroids (Pa)*

55

Cholesterol synthesis inhibitor (0.691); hypercalcemia treatment (0.686); prostate disorders treatment (0.640) Contraceptive female (0.989); antineoplastic (0.855); antiosteoporotic (0.720); ovulation inhibitor (0.685); prostate disorders treatment (0.677) Postmenopausal disorders treatment (0.669); bone formation stimulant (0.637); antiinflammatory (0.587); menopausal disorders treatment (0.550)

56

Antieczematic (0.548); prostatic (benign) hyperplasia treatment (0.518) Contraceptive female (0.951); acute neurologic disorders treatment (0.867); antineoplastic (0.833); menopausal disorders treatment (0.729) Bone formation stimulant (0.725); antiosteoporotic (0.670); ovulation inhibitor (0.665); antiinflammatory (0.661); gynecological disorders treatment (0.615); psychosexual dysfunction treatment (0.599); prostate disorders treatment (0.598); allergic conjunctivitis treatment (0.555)

57

Prostatic (benign) hyperplasia treatment (0.537); postmenopausal disorders treatment (0.512) Antiosteoporotic (0.831); antiseborrheic (0.770); antihypercholesterolemic (0.767); neuroprotector (0.733); menopausal disorders treatment (0.713) Bone formation stimulant (0.701); hypolipemic (0.678); antineoplastic (0.662); antiinflammatory (0.602); acute neurologic disorders treatment (0.601); prostate disorders treatment (0.571); ovulation inhibitor (0.565)

58

59

60

61 62

Hypolipemic (0.857); antiosteoporotic (0.831); neuroprotector (0.797); antihypercholesterolemic (0.788); antineoplastic (0.783) Immunosuppressant (0.764); antiinflammatory (0.747); analeptic (0.741); bone formation stimulant (0.658); anesthetic (0.626) Apoptosis agonist (0.600); menopausal disorders treatment (0.584); male reproductive disfunction treatment (0.567) Cholesterol synthesis inhibitor (0.555); antileukemic (0.544); prostate cancer treatment (0.528) Antiosteoporotic (0.935); antiseborrheic (0.919); menopausal disorders treatment (0.844); neuroprotector (0.844); antihypercholesterolemic (0.802) Hypolipemic (0.797); antisecretoric (0.788); bone formation stimulant (0.779); alopecia treatment (0.749); antineoplastic (0.765) Acute neurologic disorders treatment (0.752); immunosuppressant (0.729); antiinflammatory (0.692); proliferative diseases treatment (0.626) Prostate disorders treatment (0.625); anesthetic general (0.582); menstruation disorders treatment (0.553); ovulation inhibitor (0.555) Antiosteoporotic (0.960); antihypercholesterolemic (0.900); anesthetic general (0.870); respiratory analeptic (0.797); neuroprotector (0.770) Antineoplastic (0.762); hypolipemic (0.750); anticarcinogenic (0.741); bone formation stimulant (0.737); antieczematic (0.730) Cholesterol synthesis inhibitor (0.715); proliferative diseases treatment (0.710); apoptosis agonist (0.661); prostate disorders treatment (0.650) Antiacne (0.997); prostatic (benign) hyperplasia treatment (0.997); dermatologic (0.996); prostate disorders treatment (0.949) Antineoplastic (0.876); antiosteoporotic (0.668); antieczematic (0.644); anesthetic general (0.511) Antiacne (0.997); prostatic (benign) hyperplasia treatment (0.996); dermatologic (0.996); prostate disorders treatment (0.920) Antineoplastic (0.897); antiosteoporotic (0.704); antieczematic (0.657); anesthetic general (0.567); erythropoiesis stimulant (0.514) Hypolipemic (0.514)

*Only activities with Pa > 0.5 are shown

well as animals (Bartlett et al. 2017; Hori et al. 1967; Thompson 1967; Berger and Hanahan 1971; Kaneshiro 1987). A screening study of the phospholipid composition of marine as well as freshwater invertebrates has shown that ceramide 2aminoethylphosphonate (CAEP, a sphingophosphonolipid) is widely distributed primarily in molluscs (Dembitsky and Vaskosky 1976; Dembitsky 1979; Dembitsky et al. 1992, 1993, 1994; Hanus et al. 2009). Biosynthesis of 2aminoethylphosphonate, as well as catabolism, is now sufficiently well studied and the materials are presented in the form of a series of review articles (Baer 1972; Joseph 1982; Satake and Miyamoto 2012; Peck and van der Donk 2013). As has been shown by some authors, phosphono lipids are natural inhibitors of phospholipase D (Florin-Christensen et al. 1986). The big surprise is that phosphonosteroids have not been found to date in nature (McGrath et al. 2013; Dembitsky 2004; Dembitsky and Maoka 2007). Although from the point of view of logic, they must be found in the near future.

However, phosphonosteroids (34–62, structures are shown in Figs. 3 and 4, the activities are shown in Tables 2 and 3) have been synthesized, and many of them show a wide range of biological activities. A series of phosphonostroids (34–39), which are derivatives of vitamin D, has been synthesized by various authors. Thus, three steroids (34, 35, and 37) with a skeleton of vitamin D were synthesized. Synthesized steroids with 24β-hydroxy-group exhibited significant vitamin D activity in vitro induced the formation of osteoids in rats (Steinmeyer et al. 2001). Salomon and colleagues described the synthesis of diethyl [(5Z,7E)-(1S,3R)-1,3-dihydroxy-9,10-secochola-5,7,10(19)trien-23-in-24-yl]phosphonate (36) and its activity was studied. As experiments have shown, the synthetic steroid is a powerful antiproliferative vitamin D, showing the absence of calcemic effects in vivo (Salomón et al. 2011). Synthetic bisphosphonates vitamin D analogues (38 and 39) are potent inhibitors of osteoclast activation and are the first choice for

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the treatment of pathologies that affect bone metabolism, such as osteoporosis and Paget’s disease. In addition, they are also used to treat malignant tumors, such as multiple myeloma or other tumors with metastases in the bone, such as prostate and breast cancer (Steinmeyer et al. 2001; Lems and Geusens 2009; Carmel et al. 2012; Leizaola-Cardesa et al. 2016). About 50 years ago, Jean-Louis Bravet of Ottawa University conducted a synthesis of steroylphosphonates (40–45, 52, and 53 structures see Fig. 4, and activities Table 3) from estrone. The author describes the details of the synthesis however the biological activity of synthesized steroids has not been studied (Bravet 1971; Bravet et al. 1972). Steroidal phosphonates (50 and 51) as inhibitors of Leishmania promastigote, Leishmania mexicana mexicana, and Pneumocystis carinii carinii proliferation in vitro were synthesized and their activity was studied. Experiments have shown that all synthesized phosphonosteroids inhibit the growth of Leishmania promastigote, L. mexicana mexicana, and Pneumocystis carinii carinii (Beach et al. 1997). Synthesis of bile acid-bisphosphonate steroid conjugate (54) was synthesized in order to refine the new technique and synthesis conditions. The authors did not set the goal of determining biological activity (Massarenti et al. 2017). A phosphorus-containing 11β-aryl-substituted steroid (55) was synthesized and showed in vitro progesterone receptor and glucocorticoid receptor antagonist activities (Jiang et al. 2006). Steroid (56) was synthesized and used to test hormonal activity in chick embryos. The introduction of the aromatic fragment into the 11th position of the steroid had to increase the hormonal activity. However, the conducted studies did not give the expected effect (Bravet et al. 1972). Steroidal bisphosphonates (57–59) are potential inhibitors of osteoporosis were synthesized and their activity was tested and satisfactory results were obtained (Gallagher et al. 2000; Teitelbaum et al. 2011; Allen et al. 2016). It should be noted that the structure of phosphonolipids (57–60), where phosphorus has no direct connection with the core of the steroid. But nevertheless, de facto these lipids belong to the class of phosphonolipids and demonstrate interesting biological activities. An interesting cholesteryl-trisoxyethylene-bisphosphonic acid complex (60) was synthesized and used as a bone orienting fragment for liposomes. Liposomes intended for the treatment of bone-related diseases have been targeted for liposomes using cholesteryl-trisoxyethylene-bisphosphonic acid complex to achieve long-term local exposure to high concentrations of bioactive compounds, thereby increasing therapeutic efficacy and minimizing systemic side effects (Hengst et al. 2007). Both homo- and secosteroids (61 and 62) were synthesized as potential inhibitors of steroid 5αreductase (Holt 1990).

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Conclusion An interesting and rare group of natural steroid phosphate esters and synthetic phosphonosteroids presented in our review presents biological active lipid molecules that exhibit specific activities. Steroid phosphate esters have recently been isolated from marine sponges and starfish. Steroid phosphate esters were known before they were synthesized more than 50 years ago and were used as inhibitors of steroid sulphatase and especially breast cancer. The presented data show how interesting the new lipid molecules steroid phosphate esters as well as phosphonosteroids are; however, we believe that in the near future, the biosynthesis of these molecules will be studied and they will be possible candidates for use in clinical medicine as agents against breast cancer. Acknowledgements The work was performed in the framework of the Program for Basic Research of Russian 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.

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