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This research aimed to develop novel selective secosteroids that are highly active against hormone-dependent breast cancer. A simple and convenient approach to N′-acylated 13,17-secoestra-1,3,5(10)-trien-17-oic acid hydrazides was disclosed and these novel types of secosteroids were screened for cytotoxicity against the hormone-dependent human breast cancer cell line MCF7. Most secosteroid N′-benzoyl hydrazides have demonstrated high cytotoxicity against MCF7 cells with IC 50 values below 5 μM, which are superior to that of the reference drug cisplatin. Hit compounds 2c , 2e and 2i were characterized by high cytotoxicity (IC 50 = 1.6–1.9 μM) and very good selectivity towards MCF7 breast cancer cells. The lead secosteroids 2c , 2e and 2i also exhibit antiestrogenic effects and alter the expression of cell cycle regulating proteins. The effect of selected compounds on PARP (poly(ADP-ribose) polymerase) and Bcl-2 (B-cell CLL/lymphoma 2) indicates their proapoptotic potential. The synthesized secosteroids may be considered as new promising anti-breast cancer agents targeting ERα and apoptosis pathways. [Display omitted] • A series of secosteroid diacylhydrazines superior to cisplatin against MCF7 cells. • Lead secosteroids exhibit antiestrogenic effects and show high selectivity. • Lead compounds alter the expression of cell cycle regulating proteins in MCF7 cells. • Lead secosteroids cause PARP cleavage and a decrease in Bcl-2 expression. [ABSTRACT FROM AUTHOR]

Abstract The aim of the present study was to evaluate the association between Bone mineral density in lumber spine and femoral neck with serum total levels of vitamin D, sun exposure and Consumption of vitamin D Supplement in obese Saudi females aged between 30 and 54 years old. Recent attention to the high prevalence of osteoporosis and its association with low vitamin D levels in adults has raised the importance of vitamin D evaluation. A low level of vitamin D is considered to be one of the most important risk factors for osteoporosis. In this study; 120 obese Saudi females with no diagnosed chronic diseases attending the Outpatient clinic at king Khalid University hospital in Riyadh. Saudi Arabia, recruited randomly in period of 12 months. In this study, Serum levels of total Vitamin D were considered to be severe deficient if it was lower than 25 ng/mL, mild to moderate deficient if it was between 25 and 60 ng/mL and optimum level if it was 61–200 ng/mL. The results showed that; sun exposure was significantly affect and Correlate with serum level of Vitamin D in the subjects. In addition, daily consumption of Vitamin D supplement was significantly affect and Correlate with serum level of Vitamin D in the subjects of this study. Moreover, the results showed that; 50% of the age group (40–49 years old) having severe deficiency of Vitamin D. While, 50% of the age group (50–59 years old) having optimal level of Vitamin D. And these results mean that age is not Correlated with vitamin D deficiency in subjects of this study. [ABSTRACT FROM AUTHOR]

A convenient and selective approach to 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-arylcarbothioamido]hydrazides and hybrid molecules containing secosteroid and 1,2,4-triazole fragments was disclosed and these novel types of secosteroids were screened for cytotoxicity against hormone-dependent human breast cancer cell line MCF-7. Most of secosteroid–1,2,4-triazole hybrids showed significant cytotoxic effect comparable or superior to that of the reference drug cisplatin. Hit secosteroid–1,2,4-triazole hybrids 4b and 4h were characterized by high cytotoxicity and good selectivity towards MCF-7 breast cancer cells. PARP cleavage (marker of apoptosis) and ERα and cyclin D1 downregulation were discovered in MCF-7 cells treated with lead secosteroid–1,2,4-triazole hybrid 4b. The synthesized secosteroids may be considered as new promising anticancer agents. [Display omitted] • Secosteroid thiosemicarbazides and secosteroid–1,2,4-triazoles were synthesized. • A number of obtained compounds showed good cytotoxicity for MCF-7 cancer cells. • Hit compounds 4b and 4h superior to the reference drug cisplatin. • Hit compound 4b caused PARP cleavage and ERα and cyclin D1 downregulation. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Mini review is devoted to highly oxygenated isoprenoid lipids that are produced by fungi and fungal endophytes. • Fungal endophytes were obtained from brown and red algae, marine invertebrates and/or from marine sediments. • Highly oxygenated isoprenoid lipids have the pharmacological potential on anti-hypercholesterolemic, anti-neoplastic, anti-eczematic and anti-inflammatory activity estimated with a confidence of 84–90%. Abstract This mini review is devoted to highly oxygenated isoprenoid lipids (HOIL) that are produced by fungi and fungal endophytes from various ecological niches, both terrestrial and aquatic. Steroids were distributed as from edible cultivated fungi, as well as fungi collected in forests. Fungal endophytes were generally isolated from plants and cultured to obtain sufficient biomass. Marine fungi were obtained from marine brown and red algae and marine invertebrates such as sponges, corals, worms, crustacea or from marine sediments. HOIL isolated from the terrestrial ecosystem have the pharmacological potential on anti-hypercholesterolemic, anti-neoplastic, anti-eczematic and anti-inflammatory activity estimated with a confidence of 84–90%. HOIL that produced by marine fungal species are predicted as having anti-inflammatory and anti-hypercholesterolemic activity with a confidence of 82–91%. In addition, they may have potential acetylcholinesterase and cell adhesion molecule inhibitors estimated with a confidence of 86–88%. [ABSTRACT FROM AUTHOR]

On the basis of the literature data, our previous research work and docking experiments, we designed novel 19-norvitamin D compounds having elongated 2-alkylidene substituents. These 19-norcalcitriol derivatives have attached 2-(3′-aminopropylidene) substituent in which the nitrogen atom bears acyl residue derived from succinic acid and l -methionine. Both compounds were obtained by the same synthetic strategy involving Julia coupling of the A-ring ketone with the known C/D-ring sulfone. In the obtained 1α,25-dihydroxy-19-norvitamin D 3 derivative, the alkylidene substituent at C-2 was further elaborated to the desired structures. [ABSTRACT FROM AUTHOR]

Pronounced biological potency of 19-norvitamin D compounds as well as interesting biological action of the vitamin D analogs possessing elongated side chains encouraged us to expand the scope of our structure-activity studies to encompass such modifications of the 1α,25-(OH) 2 D 3 (calcitriol) molecule. The aim of our studies was the synthesis of calcitriol analog, designed on the basis of results of molecular modeling and docking experiments, and characterized by a presence of a long, nitrogen-containing substituent attached to carbon 26, and an exomethylene moiety transferred from C-10 to C-2. The convergent synthesis of such 19-norcalcitriol compound, described in this communication, consisted of the preparation and combining four building blocks. The crucial point of the synthesis, coupling of the known A-ring phosphine oxide and the synthesized Grundmann ketone analog, was achieved using Wittig-Horner protocol. It provided the protected analog of 1α,25-dihydroxy-2-methylene-19-norvitamin D 3 which was further transformed into the target compound. [ABSTRACT FROM AUTHOR]

Prompted by results of molecular modeling performed on the seco - d -ring-vitamins D, we turned our attention to such analogs, having reversed configurations at C-13 and C-14, as the next goals of our studies on the structure-activity relationship for vitamin D compounds. First, we developed an efficient total synthesis of the “upper” C/ seco - d -ring fragment with a 7-carbon side chain. Then, we coupled it with A-ring fragments using Sonogashira or Wittig-Horner protocol, providing the targeted D- seco analogs of 1α,25-dihydroxyvitamin D 3 and 1α,25-dihydroxy-19-norvitamin D 3 possessing a vinyl substituent at C-14 and a double bond between C-17 and C-20. The affinities of the synthesized vitamin D analogs to the full-length recombinant rat VDR were examined, as well as their differentiating and transcriptional activities. In these in vitro tests, they were significantly less active compared to 1α,25-(OH) 2 D 3 . Moreover, it was established that the analogs tested in vivo in rats showed no calcemic potency. [ABSTRACT FROM AUTHOR]

As a continuation of our efforts directed to the structure-activity relationship studies of vitamin D compounds, we present in this paper the synthesis of new analogues of 1α,25-(OH) 2 D 3 characterized by numerous structural modifications, especially a cleaved D ring. Total synthesis of the CD fragment required for the construction of the target vitamins was based on the Stork approach. The structure of the key intermediate – bicyclic hydroxy lactone – was established by crystallographic and electronic circular dichroism (ECD) spectral analysis. Following the attachment of the hydroxyalkyl side chain, the formed D-seco Grundmann ketone was subjected to Wittig-Horner coupling with the corresponding A-ring phosphine oxides providing two desired D-seco analogues of 19-nor-1α,25-(OH) 2 D 3 , one without a substituent at C-2 and the other possessing a 2-exomethylene group. Both compounds were biologically tested and the latter was found to be more active in in vitro tests. Despite so many structural changes introduced in its structure, the biological activity of the 2-methylene analogue approached that of the natural hormone. The synthesized D-seco vitamins, however, proved to be inactive on bone and intestine in vivo . [ABSTRACT FROM AUTHOR]

An elegant approach to unknown secosteroid–quinoline hybrids is disclosed. A series of 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N′-(iso)quinolylmethylene]hydrazides was prepared and these novel type of secosteroids was screened for antiproliferative activity against estrogen-responsive human breast cancer cell line MCF-7. Most of the synthesized compounds showed a cytotoxic effect superior to that of reference drug cisplatin; the lead compound exhibits the highest activity with the IC 50 value of about 0.8 μM and is 7 times more active than cisplatin. A high selectivity index was observed for the hit 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N′-quinolylmethylene]hydrazides 2a and 2c. Compounds 2a and 2c evaluated in luciferase reporter assays exhibited high antiestrogenic potency which was superior to that of tamoxifen. These hit compounds were characterized by high activity against MCF-7 cells that retained towards multidrug-resistant NCI/ADR-RES cells. [Display omitted] • A broad series of secosteroid–quinoline hybrids highly active towards MCF-7 breast cancer cells were synthesized. • A number of obtained compounds were 2–7 times more active than the reference drug cisplatin. • Hit compounds 2a and 2c showed high cytotoxicity for MCF-7 cells and multidrug-resistant NCI/ADR-RES cancer cells. • Compounds 2a and 2c tested in luciferase reporter assays exhibited high antiestrogenic potency. [ABSTRACT FROM AUTHOR]

The mammalian skin is a heterogeneous organ/tissue covering our body, showing regional variations and endowed with neuroendocrine activities. The latter is represented by its ability to produce and respond to neurotransmitters, neuropeptides, hormones and neurohormones, of which expression and phenotypic activities can be modified by ultraviolet radiation, chemical and physical factors, as well as by cytokines. The neuroendocrine contribution to the responses of skin to stress is served, in part, by local synthesis of all elements of the hypothalamo-pituitary–adrenal axis. Skin with subcutis can also be classified as a steroidogenic tissue because it expresses the enzyme, CYP11A1, which initiates steroid synthesis by converting cholesterol to pregnenolone, as in other steroidogenic tissues. Pregnenolone, or steroidal precursors from the circulation, are further transformed in the skin to corticosteroids or sex hormones. Furthermore, in the skin CYP11A1 acts on 7-dehydrocholesterol with production of 7-dehydropregnolone, which can be further metabolized to other Δ7steroids, which after exposure to UVB undergo photochemical transformation to vitamin D like compounds with a short side chain. Vitamin D and lumisterol, produced in the skin after exposure to UVB, are also metabolized by CYP11A1 to several hydroxyderivatives. Vitamin D hydroxyderivatives generated by action of CYP11A1 are biologically active and are subject to further hydroxylations by CYP27B1, CYP27A1 and CP24A. Establishment of which intermediates are produced in the epidermis in vivo and whether they circulate on the systemic level represent a future research challenge. In summary, skin is a neuroendocrine organ endowed with steroid/secosteroidogenic activities [ABSTRACT FROM AUTHOR]

The electrochemical behavior of vitamins D2 and D3 were examined by performing cyclic voltammetry (CV), rotating disk electrode voltammetry, controlled potential electrolysis and chemical oxidation in aprotic organic solvents. Both vitamins were electrochemically oxidized in dichloromethane and acetonitrile (Epox ~ +0.8 vs. (Fc/Fc+)/V, where Epox is the anodic peak potential and Fc=ferrocene) via a one-electron chemically irreversible process on the short voltammetric time scale (↜seconds). Varying the scan rate (0.1Vs-1 to 20Vs-1) and temperature (233K to 293K) did not strongly affect the voltammetric response recorded on platinum and glassy carbon electrode surfaces with the oxidation process remaining chemically irreversible over the range of scan rates and temperatures tested, indicating that the initially formed cation radical was not long-lived. Repetitive CV experiments indicated that the oxidized product partially adsorbed onto the electrode surface, resulting in diminishing peak currents with multiple scans. Bulk controlled potential electrolysis of the vitamin D compounds performed by alternating several cycles of oxidative electrolysis and reductive pulsed stripping proved to be effective in stripping the adsorbed species off the electrode surfaces. Longer time scale bulk electrolysis experiments led to the detection of a new oxidation peak appearing at less positive potentials as the electrolysis progressed, suggesting that the compounds underwent oxidation on long time scales (minutes to hours) via a two electron process. The vitamins were most likely initially oxidized via one-electron (E-step) to form a cation radical, which reacts homogeneously in two chemical steps (C-steps) where one chemical step is fast (< 1 s) and one is relatively slow (> 1 s). On the electrolysis timescale, the oxidized product then undergoes a second electron transfer (E) at less positive potentials, so the overall mechanism is an ECCE process. Chemical oxidation of vitamin D3 with 2mol equiv of the one-electron oxidant, NO+SbF6- in acetonitrile/dichloromethane 1:4 ratio (v/v) resulted in the complete oxidation of the starting material in an overall two-electron process, with NMR analysis of the reaction mixture indicating that the triene moiety is absent from the products. [ABSTRACT FROM AUTHOR]

Abstract: We have synthesized 3β,21-dihydroxypregna-5,7-dien-20-one (21(OH) 7DHP) and used UVB radiation to induce its photoconversion to analogues of vitamin D (pD), lumisterol (pL) and tachysterol (pT). The number and character of the products and the dynamics of the process were dependent on the UVB dose. The main products: pD and pT compounds were characterized by UV absorption, MS and NMR spectroscopy after RP-HPLC chromatography. In addition, formation of multiple oxidized derivatives of the primary products was detected and one of these derivatives was characterized as oxidized 21-hydroxyisotachysterol compound (21(OH)oxy-piT). These newly synthesized compounds inhibited growth of human melanoma cells in a dose dependent manner, with greater or equal potency to calcitriol. 3β,21-Dihydroxy-9β,10α-pregna-5,7-dien-20-one (21(OH)pL) and 21(OH)oxy-piT had higher potency against pigmented melanoma cells, while the EC50 for compounds 21(OH)7DHP and (5Z,7E)-3β,21-dihydroxy-9,10-secopregna-5,7,10(19)-trien-20-one (21(OH)pD) were similar in both pigmented and non-pigmented cells. Moreover, 21(OH)7DHP and its derivatives inhibited proliferation of human epidermal HaCaT keratinocytes, albeit at a lower activity compared to melanoma cells. Importantly, 21(OH)7DHP derivatives strongly inhibited the colony formation of human melanoma cells with 21(OH)pD being the most potent. The potential mechanism of action of newly synthesized compounds was similar to that mediated by 1,25(OH)2D3 and involved ligand-induced translocation of vitamin D receptor into the nucleus. In summary, we have characterized for the first time products of UVB-induced conversion of 21(OH)7DHP and documented that these compounds have selective, inhibitory effects on melanoma cells. [Copyright &y& Elsevier]

Abstract: Pregna-5,7-dienes and their hydroxylated derivatives can be formed in vivo when there is a deficiency in 7-dehydrocholesterol (7-DHC) Δ-reductase function, e.g., Smith–Lemli–Opitz syndrome (SLOS). Ultraviolet B (UVB) radiation induces photoconversion of 7-DHC to vitamin D3, lumisterol3 and tachysterol3. Two epimers (20R and 20S) of pregna-5,7-diene-3β,17α,20-triol (4 R and 4 S , respectively) were synthesized and their UVB photo-conversion products identified as corresponding 9,10-secosteroids with vitamin D-like and tachysterol-like structures, and 5,7-dienes with inverted configuration at C-9 and C-10 (lumisterol-like). The number and character of the products and the dynamics of the process were dependent on the UVB dose. At high UVB doses, the formation of multiple oxidized derivatives of the primary products, and the formation of 5,7,9(11)-triene, were observed. The production of vitamin D-like, tachysterol-like and lumisterol-like derivatives was also observed in human skin treated with 4 R and 4 S , and subjected to UV irradiation, as shown by RP-HPLC. Newly synthesized compounds inhibited melanoma growth in dose dependent manner, and some of them showed equal or higher potency than 1,25(OH)2D3. In summary, we have characterized for the first time the products of UV induced conversion of pregna-5,7-diene-3β,17α,20-triols and documented that the newly synthesized compounds have antiproliferative properties against melanoma cells. [Copyright &y& Elsevier]

Abstract: A number of 5,10-seco analogs of testosterone has been synthesized starting from products of the radical oxidation of 3β,17β-diacetoxy-5α-androstan-5α-ol. The obtained compounds possess a flexible 10-membered ring with substituents (3;OH) at C-3 and C-5. Similar derivatives with an (E)- and (Z)-Δ1(10)-double bond have been prepared also. X-ray analysis and a combination of NMR experiments have been used for their structure elucidation and conformation analysis. [Copyright &y& Elsevier]

Abstract: Seven new C-secosteroids were isolated from the gorgonian Tripalea clavaria collected from the South Atlantic. These compounds have a Δ5, 9,11-secosteroid nucleus together with a 22S hydroxyl group. The absolute configuration of the 22-hydroxyl group was determined with the help of COSY spectra of the Mosher esters of the compounds. [Copyright &y& Elsevier]

Abstract: Three new products have been isolated from the lead-tetraacetate version of the hypoiodite oxidation of 3β,17β-diacetoxy-5-hydroxy-5α-androstane. Along with the expected 1(10)-unsaturated 5,10-seco steroidal 5-ketones, the fragmentation reaction gave two epimeric C-4 iodides. Their structural assignment was based on X-ray data of one of them ((4R,10S)-4-iodo-3β,17β-diacetoxy-5,10-secoandrostan-5-one). The third new product was found to be the 5β,6β-epoxide resulting from the dehydration of the tertiary alcohol followed by epoxidation of the intermediate Δ5-olefin. [Copyright &y& Elsevier]

A number of testosterone analogs with a 13,14-secosteroidal fragment have been prepared from (13S)-13-iodo-6β-methoxy-3α, 5-cyclo-13,14-seco-5α-androstan-14,17-dione. The key steps involved stereoselective deiodination of the starting compound with triphenylphosphine and selective protection of the 17-keto group with trimethylsilylcyanide. Removal of iodine at C-13 proceeded with inversion of the configuration at C-13, which has been established by X-ray crystallography. 13,14-Secotestosterone analogues substituted and non-substituted at C-14 have been prepared. The obtained compounds containing flexible CD ring fragments are of great interest for comparative studies in biological tests together with testosterone and other steroids with a rigid tetracyclic skeleton. [Copyright &y& Elsevier]

A synthetic methodology for the synthesis of 13,14-seco-steroids with substituents at C-14 and C-17 is described. The approach involves Grob fragmentation of 14β-hydroxy-17β-tosylates, hydroboration–oxidation of the intermediate Δ13(17)-olefin, and hydride reduction of the 14-ketone. An unambiguous structural assignment of (13R,14S,17S)-14,17-diacetoxy-3-methoxy-7α-methyl-13,14-secoestra-1,3,5(10)-triene was determined by X-ray analysis. [Copyright &y& Elsevier]

A novel chemical construction of B,B-dinor-B-secosteroids as simplified cardenolide analogs, starting from the Hajos–Parrish diketone was developed. The synthesis of the equivalent of the steroid A ring was carried out through a Diels–Alder reaction between an appropriate hydroindenyl acrylate derivative and Danishefsky''s diene. [Copyright &y& Elsevier]

CYP11A1, a member of the cytochrome P450 family, plays several key roles in the human body. It catalyzes the first and rate-limiting step in steroidogenesis, converting cholesterol to pregnenolone. Aside from the classical steroidogenic tissues such as the adrenals, gonads and placenta, CYP11A1 has also been found in the brain, gastrointestinal tract, immune systems, and finally the skin. CYP11A1 activity in the skin is regulated predominately by StAR protein and hence cholesterol levels in the mitochondria. However, UVB, UVC, CRH, ACTH, cAMP, and cytokines IL-1, IL-6 and TNFα can also regulate its expression and activity. Indeed, CYP11A1 plays several critical roles in the skin through its initiation of local steroidogenesis and specific metabolism of vitamin D, lumisterol, and 7-dehydrocholesterol. Products of these pathways regulate the protective barrier and skin immune functions in a context-dependent fashion through interactions with a number of receptors. Disturbances in CYP11A1 activity can lead to skin pathology. • CYP11A1 is expressed and enzymatically active in the skin. • CYP11A1 initiates local steroidogenesis, secosteroidogenesis and 5,7-diene metabolism. • Cutaneous CYP11A1 is regulated by UVB, UVC, CRH, ACTH, c-AMP and cytokines. • CYP11A1 plays a key role in regulation of the protective barrier and immune functions. • Disturbances to CYP11A1 catalytic activity can lead to skin pathology. [ABSTRACT FROM AUTHOR]