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This article explores the diverse array of biologically active compounds derived from microbial symbionts, particularly focusing on the isolation and characterization of diepoxides, highly oxygenated triterpenoids, secosteroids, ergostane-type steroids, and meroterpenoids from various marine and plant-derived fungi. We highlight significant discoveries such as vitamin D variants from fungal species, unique sesterterpenoids from mangrove endophytic fungi, and secosteroids with potential medicinal applications. The study delves into the structural uniqueness and bioactivities of these compounds, including their anti-inflammatory, antibacterial, antifungal, antiviral, and cytotoxic effects. Notable findings include the isolation of compounds with significant activity against cancer cell lines, the inhibition of acetylcholinesterase, and promising antifouling properties. This work underscores the potential of microbial symbionts as a rich source of novel bioactive compounds with diverse therapeutic applications, highlighting the importance of marine and fungal biodiversity in drug discovery and development. [ABSTRACT FROM AUTHOR]

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]

Steroids are good candidates for drug development, thanks to their low general toxicity and possibility for structure modifications connected with change of their activity. Several 16,17-secoandrost-4-ene-16,17a-dinitrile compounds were synthesized and screened for anticancer effect previously, including 6-oxo and 6-hydroxyimino compounds. This research is continued with the attempts for different synthetic strategy and evaluation of anticancer effect mechanism. Synthesis of 3-hydroxyimino compounds was successful, but inseparable mix of isomers was excluded from biological tests. Tested secodinitriles expressed cytotoxic effect on HeLa cervix cancer cells as a model system, with submicromolar to molar IC50 values, where 6-substituted derivatives were more effective. After 72 h treatment with equitoxic concentrations equal IC50 values of test compounds the mechanism of this effect was studied using flow cytometry and specific fluorescent dyes. Modest change in both G0/G1 and G2/M resting phases and change in mitochondrial membrane potential were noticed, while the most pronounced effect was apoptosis induction. Total apoptosis was in range 50.72–58.31 % in all cell samples treated with secodinitriles, compared to 7.44 % in control samples. Total percent of dead cells, including both apoptotic and necrotic, ranged from 55.24 to 65.34 %, compared to 10.68 % in control. Selectivity towards cancer cells is very important feature of these compounds indicating their potential use as lead compounds in the drug development for the treatment of cancers of steroid hormone-dependent tissues.

Phytopathogenic fungi are among the main causes of productivity losses in agriculture. To date, synthetic chemical pesticides, such as hydroxyanilides, anilinopyrimidines and azole derivatives, represent the main treatment tools for crop plant defence. However, the large and uncontrolled use of these substances has evidenced several side effects, namely the resistance to treatments, environmental damage and human health risks. The general trend is to replace chemicals with natural molecules in order to reduce these side effects. Moreover, the valorisation of agri-food industry by-products through biotransformation processes represents a sustainable alternative to chemical synthesis in several sectors. This research is aimed at comparing the anti-phytopathogenic activity of waste bovine and porcine bile with secosteroids obtained by biotransformation of bile acids with Rhodococcus strains. The ultimate goal is to apply these natural products on food crops affected by phytopathogenic fungi. [ABSTRACT FROM AUTHOR]

Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson's disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4months of age, approximately 10months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.

Physalin H (PH), a withanolide isolated from Physalisangulata L. has been reported to have anti-inflammatory effect. However, its impact on acute lung injury (ALI) remains unexplored. In this study, we observed that PH significantly alleviated inflammation in LPS-stimulated macrophages by suppressing the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and down-regulating the expression of the inflammation-related genes. RNA sequencing analysis revealed a significant up-regulation of the NRF2 pathway by PH. Further investigation elucidated that PH attenuated the ubiquitination of NRF2 by impeding the interaction between NRF2 and KEAP1, thereby facilitating NRF2 nuclear translocation and up-regulating the expression of target genes. Consequently, it regulated redox system and exerted anti-inflammatory effect. Consistently, PH also significantly alleviated pathological damage and inflammation in LPS-induced ALI mice model, which could be reversed by administration of an NRF2 inhibitor. Collectively, these results suggest that PH ameliorates ALI by activating the KEAP1/NRF2 pathway. These findings provide a foundation for further development of pH as a new anti-inflammatory agent for ALI therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

9,10-Secosteroids are an important group of marine steroids with diverse biological activities. Herein, we report a chemoenzymatic strategy for the concise, modular, and scalable synthesis of ten naturally occurring 9,10-secosteroids from readily available steroids in three to eight steps. The key feature lies in utilizing a Rieske oxygenase-like 3-ketosteroid 9α-hydroxylase (KSH) as the biocatalyst to achieve efficient C9-C10 bond cleavage and A-ring aromatization of tetracyclic steroids through 9α-hydroxylation and fragmentation. With synthesized 9,10-secosteroides, structure-activity relationship was evaluated based on bioassays in terms of previously unexplored anti-infective activity. This study provides experimental evidence to support the hypothesis that the biosynthetic pathway through which 9,10-secosteroids are formed in nature shares a similar 9α-hydroxylation and fragmentation cascade. In addition to the development of a biomimetic approach for 9,10-secosteroid synthesis, this study highlights the great potential of chemoenzymatic strategies in chemical synthesis., (© 2024 Wiley‐VCH GmbH.)

Steroids have long been sought after as synthetic targets. Their rearranged counterparts, though, have only recently received more attention, when isolation and biological testing programs revealed several molecular entities that were both structurally intriguing as well as biologically relevant. This review will highlight contemporary synthetic approaches towards the growing class of seco- and abeo -steroids and some related triterpenoid natural products. 1 Introduction 2 Cyclocitrinol 2.1 Li's Synthesis of Cyclocitrinol 2.2 Gui's Synthesis of Cyclocitrinol 3 Strophasterol 3.1 Heretsch's Synthesis of Strophasterol A 3.2 Kuwahara's Synthesis of Strophasterols A and B 4 Pleurocin A/Matsutakone and Pleurocin B 4.1 Heretsch's Synthesis of Pleurocin A/Matsutakone and Pleurocin B 5 Aplysiasecosterol A 5.1 Li's Synthesis of Aplysiasecosterol A 6 Glaucogenins C and D 6.1 Tian's Syntheses of 5,6-Dihydro-glaucogenin C and Glaucogenin D 7 Physalin B 7.1 Sodeoka's Synthesis of the DFGH Ring System of Physalin B 8 Limonin 8.1 Hirama's Synthesis of (±)-Limonin 9 Schiglautone A 9.1 Ding's Synthesis of (±)- atrop -Schiglautone A 10 Conclusion [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]

Octocoral Sinularia leptoclados has been identified as a source of bioactive 9,11-secosteroids. This study adopted a targeted isolation approach to the discovery and analysis of five 9,11-secosteroids, including two novel compounds named sinleptosterols A (1) and B (2) as well as five known analogues (8αH-3β,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9-one (3), 8βH-3β,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9-one (4), leptosterol A (5), (24S)-3β,11-dihydroxy-24-methyl-9,11-secocholest-5-en-9-one (6), and 3β,11-dihydroxy-9,11-secogorgost-5-en-9-one (7)) in terms of 1H-NMR patterns and potency against neutrophilic inflammation. The structure of secosteroids 1 and 2 was deduced from general spectroscopic analysis and an examination of NMR spectra. Among the above-mentioned isolates, compound 4 had the most pronounced effect in inhibiting elastase release and superoxide anion generation, with the IC50 values of 2.96 and 1.63 μM, respectively.

We performed a high-content screening (HCS) assay aiming to discover bioactive molecules with proteasome inhibitory activity. By structural elucidation, we identified six compounds purified from soft coral Clavularia flava, which potentiates proteasome inhibition. Chemical structure elucidation revealed they are dolabellane- and secosteroid-based compounds including a new dolabellane, clavinflol C (1), three known dolabellanes, stolonidiol (2), stolonidiol-17-acetate (3), and clavinflol B (4) as well as two new secosteroids, 3β,11-dihydroxy-24-methyl-9,11-secocholest-5-en-9,23-dione (5) and 3β,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9,23-dione (6). All six compounds show less cytotoxicity than those of known proteasome inhibitors, bortezomib and MG132. In summary, the high-content measurements of control inhibitors, bortezomib and MG132, manifest the highest ratio >2 in high-content measurement. Of the isolated compounds, 2 and 5 showed higher activity, followed by 3 and 6, and then 1 and 4 exhibited moderate inhibition.

We previously examined the cellular uptake of six types of vitamin D in human intestinal Caco-2 cells. Since vitamins D 5 -D 7 were commercially unavailable, we synthesized these compounds organically before studying them. This process led us to understand that new secosteroids could be generated as vitamin D candidates, depending on the sterol used as the starting material. We obtained two new secosteroids-compounds 3 and 4 -from fucosterol in the current study. We investigated the intestinal absorption of these compounds using Caco-2 cells cultured in Transwells and compared the results with vitamin D 3 , a representative secosteroid. The intestinal absorption of compound 4 was comparable to that of vitamin D 3 . Compound 3 showed similar uptake levels but transported about half as much as vitamin D 3 . These compounds demonstrated intestinal absorption at the cellular level. Vitamin D is known for its diverse biological activities manifest after intestinal absorption. Using PASS online simulation, we estimated the biological activity of compound 3 's activated form. In several items indicated by PASS, compound 3 exhibited stronger biological activity than vitamins D 2 -D 7 and was also predicted to have unique biological activities.

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]

The first B-ring 5,6-secosteroid isolated from plants was obtained from Frankenia foliosa, growing in Australia's arid zone. This rare secosteroid was shown to be active against all cell lines including head and neck squamous cell carcinoma (SCC) cancer cell lines that contain the Cdc25A phosphatase protein. [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]

Marine environments are a rich source of significant bioactive compounds. The Hawaiian archipelago, located in the middle of the Pacific Ocean, hosts diverse microorganisms, including many endemic species. Thirty-eight microbial extracts from Hawaiian coastal waters were evaluated for their antiviral activity against four mammalian viruses including herpes simplex virus type one (HSV-1), vesicular stomatitis virus (VSV), vaccinia virus and poliovirus type one (poliovirus-1) using in vitro cell culture assay. Nine of the 38 microbial crude extracts showed antiviral potencies and three of these nine microbial extracts exhibited significant activity against the enveloped viruses. A secosteroid, 5α(H),17α(H),(20R)-beta-acetoxyergost-8(14)-ene was putatively identified and confirmed to be the active compound in these marine microbial extracts. These results warrant future in-depth tests on the isolation of these active elements in order to explore and validate their antiviral potential as important therapeutic remedies.

The total synthesis of aplysiasecosterols A and B has been accomplished. Key features of the synthesis include the Suzuki-Miyaura coupling of each AB-ring segment and common D-ring segment. The AB-ring segment of aplysiasecosterol B was synthesized by Shi asymmetric epoxidation as a key reaction. The common D-ring segment was constructed by stereoselective hydrogenation and Sharpless asymmetric dihydroxylation as key reactions. This late-stage convergent synthesis, which has rarely been reported in secosteroid synthesis, can be adapted to many 9,11-secosteroids.

Abstract: Starting from estrone 3-benzyloxy-17-hydroxy-16,17-secoestra-1,3,5(10)-triene- 16-nitrile (1) was synthesized in several synthetic steps. This compound was the key intermediate in the syntheses of other 17-substituted-16,17-secoestrone derivatives. Among them 3-hydroxy-17-bromo-16,17-secoestra-1,3,5(10)-triene-16-nitrile (5) is of special interest, because of its antiestrogenic activity, with no estrogenic properties. For this reason an alternative pathway for the synthesis of this compound was sought. The structures of 3-benzyloxy-17-bromo-16,17-secoestra-1,3,5(10)-triene- 16-nitrile (compound 2) and 3-hydroxy-17-p-toluenesulphonyloxy-16,17-secoestra 1,3,5(10)-triene-16-nitrile (compound 4), intermediates in the two different synthetic pathways used to obtain the desired compound 5, were unambiguously proved by appropriate X-ray structural analyses. The puckering, asymmetry parameters and torsion angles of compounds 2 and 4 are discussed and molecular-mechanic calculations for them were performed.

Altersteroids A-D ( 1 - 4 ), four new 9,11-secosteroid-derived γ-lactones, were isolated from cultures of the ascomycete fungus Alternaria sp. Their structures were elucidated primarily by NMR experiments. The absolute configuration of 1 was established by X-ray crystallographic analysis of its di- p -nitrobenzenesulfonate 1a using Cu Kα radiation, whereas those for 2 - 4 were assigned by quantum-chemical calculations. Compounds 1 - 4 incorporate a γ-lactone moiety fused to the steroid D ring at C-13/C-14. Compound 3 showed moderate cytotoxicity toward four tumor cell lines and induced an apoptotic process in A549 cells. Notably, compound 3 showed equipotent activity against the cisplatin-sensitive MB49 and -resistant MB49 CisR cells, with an IC 50 value of 12.7 μM.

From diethyl ether fraction of the Red Sea soft coral, Litophyton arboreum, two new terpenoidal derivatives, himachalene-type sesquiterpene (3α,6α-epidioxyhimachal-1-ene, 1) and secosteroidal derivative (22-norerogostane derivative, 13,14-seco-22-norergosta-4,24(28)-dien-19-hydroperoxide-3-one, 2), were identified. In addition to di-acetyl cembranoid derivative, ( 3) was isolated for the first time from the nature. Along with three known metabolites, sarcophytol M ( 4), 7β-acetoxy-24-methylcholesta-5-24(28)-diene-3,19-diol ( 5) and erythro- N-dodecanoyl-docosasphinga-(4 E,8 E)-dienine ( 6) were obtained. Spectroscopic measurements including 1D and 2D NMR were used for identification of chemical structures. All compounds were evaluated to assess their antiproliferative effect toward three different cancer cell lines MCF-7 (human breast carcinoma), HCT116 (human colon cancer) and HepG-2 (human hepatic carcinoma) in comparison with standard anticancer drug (Doxorubicin) by employing SRD assay. Compound 3 showed significant antiproliferative activities to MCF-7 (IC 19.1 ± 0.032 µM), to HepG2 (IC 24.0 ± 0.032 µM) and to HCT116 (IC 22.0 ± 0.092 µM). The antiproliferative activities of 3 can be attributed, at least partly, to their ability to do cell cycle arrest, particularly, in G0/G1 and S phases. [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]

Deregulated melanogenesis is involved in melanomagenesis and melanoma progression and resistance to therapy. Vitamin D analogs have anti-melanoma activity. While the hypercalcaemic effect of the active form of Vitamin D (1,25(OH)2D3) limits its therapeutic use, novel Vitamin D analogs with a modified side chain demonstrate low calcaemic activity. We therefore examined the effect of secosteroidal analogs, both classic (1,25(OH)2D3 and 25(OH)D3), and novel relatively non-calcemic ones (20(OH)D3, calcipotriol, 21(OH)pD, pD and 20(OH)pL), on proliferation, colony formation in monolayer and soft-agar, and mRNA and protein expression by melanoma cells. Murine B16-F10 and hamster Bomirski Ab cell lines were shown to be effective models to study how melanogenesis affects anti-melanoma treatment. Novel Vitamin D analogs with a short side-chain and lumisterol-like 20(OH)pL efficiently inhibited rodent melanoma growth. Moderate pigmentation sensitized rodent melanoma cells towards Vitamin D analogs, and altered expression of key genes involved in Vitamin D signaling, which was opposite to the effect on heavily pigmented cells. Interestingly, melanogenesis inhibited ligand-induced Vitamin D receptor translocation and ligand-induced expression of VDR and CYP24A1 genes. These findings indicate that melanogenesis can affect the anti-melanoma activity of Vitamin D analogs in a complex manner. [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]