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Guillaume Médard - One of the best experts on this subject based on the ideXlab platform.
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a route to the 9 10 Secosteroid astrogorgiadiol featuring a key sp2 sp3 suzuki type cross coupling
ChemInform, 2014Co-Authors: Guillaume MédardAbstract:Starting from (+)-vitamin D3 (I) to construct the CD ring building block (II) a practical semi-synthesis of the title compound (VI) is developed.
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A Route to the 9,10‐Secosteroid Astrogorgiadiol Featuring a Key sp2—sp3 Suzuki Type Cross‐Coupling.
ChemInform, 2014Co-Authors: Guillaume MédardAbstract:Starting from (+)-vitamin D3 (I) to construct the CD ring building block (II) a practical semi-synthesis of the title compound (VI) is developed.
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A route to the 9,10-Secosteroid astrogorgiadiol featuring a key sp2–sp3 Suzuki type cross-coupling
Tetrahedron, 2014Co-Authors: Guillaume MédardAbstract:Abstract The described semi-synthetic route differs from the previously published approaches by an original C-7–C-8 disconnection. The kinetic enol triflate of Grundmann ketone was chosen as the CD-ring platform on which to couple an A-ring synthon via a challenging sp2–sp3 cross-coupling. A range of A-ring synthons was synthesized to allow the investigations of various conditions of metal-catalyzed couplings. Suzuki-type chemistry provided a useful (89% yield) answer. Whereas the last step of the designed route—a regioselective opening of the epoxide obtained from the alkene, product of the coupling reaction—proved more challenging than expected, a hydroboration endgame route completed a formal synthesis of (−)-astrogorgiadiol.
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a route to the 9 10 Secosteroid astrogorgiadiol featuring a key sp2 sp3 suzuki type cross coupling
Tetrahedron, 2014Co-Authors: Guillaume MédardAbstract:Abstract The described semi-synthetic route differs from the previously published approaches by an original C-7–C-8 disconnection. The kinetic enol triflate of Grundmann ketone was chosen as the CD-ring platform on which to couple an A-ring synthon via a challenging sp2–sp3 cross-coupling. A range of A-ring synthons was synthesized to allow the investigations of various conditions of metal-catalyzed couplings. Suzuki-type chemistry provided a useful (89% yield) answer. Whereas the last step of the designed route—a regioselective opening of the epoxide obtained from the alkene, product of the coupling reaction—proved more challenging than expected, a hydroboration endgame route completed a formal synthesis of (−)-astrogorgiadiol.
Andrzej Slominski - One of the best experts on this subject based on the ideXlab platform.
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detection of novel cyp11a1 derived Secosteroids in the human epidermis and serum and pig adrenal gland
Scientific Reports, 2015Co-Authors: Andrzej Slominski, Wei Li, Edith K Y Tang, Arnold E Postlethwaite, Elaine W Tieu, Robert C TuckeyAbstract:To investigate whether novel pathways of vitamin D3 (D3) and 7-dehydrocholesterol (7DHC) metabolism initiated by CYP11A1 and previously characterized in vitro, occur in vivo, we analyzed samples of human serum and epidermis, and pig adrenals for the presence of intermediates and products of these pathways. We extracted human epidermis from 13 individuals and sera from 13 individuals and analyzed them by LC/qTOF-MS alongside the corresponding standards. Pig adrenal glands were also analyzed for these steroids and Secosteroids. Epidermal, serum and adrenal samples showed the presence of D3 hydroxy-derivatives corresponding to 20(OH)D3, 22(OH)D3, 25(OH)D3, 1,25(OH)2D3, 20,22(OH)2D3, 20,23(OH)2D3, 20,24(OH)2D3, 20,25(OH)2D3, 20,26(OH)2D3, 1,20,23(OH)3D3 and 17,20,23(OH)3D3, plus 1,20(OH)2D3 which was detectable only in the epidermis. Serum concentrations of 20(OH)D3 and 22(OH)D3 were only 30- and 15-fold lower than 25(OH)D3, respectively, and at levels above those required for biological activity as measured in vitro. We also detected 1,20,24(OH)3D3, 1,20,25(OH)3D3 and 1,20,26(OH)3D3 in the adrenals. Products of CYP11A1 action on 7DHC, namely 22(OH)7DHC, 20,22(OH)27DHC and 7-dehydropregnenolone were also detected in serum, epidermis and the adrenal. Thus, we have detected novel CYP11A1-derived Secosteroids in the skin, serum and adrenal gland and based on their concentrations and biological activity suggest that they act as hormones in vivo.
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Novel non-calcemic Secosteroids that are produced by human epidermal keratinocytes protect against solar radiation.
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Andrzej Slominski, Wei Li, Zorica Janjetovic, Piotr Wasilewski, Sofia Rosas, Sherie Hanna, Robert M. Sayre, John C. Dowdy, Robert C TuckeyAbstract:Abstract CYP11A1 hydroxylates the side chain of vitamin D3 (D3) in a sequential fashion [D3 → 20 S (OH)D3 → 20,23(OH) 2 D3 → 17,20,23(OH) 3 D3], in an alternative to the classical pathway of activation [D3 → 25(OH)D3 → 1,25(OH) 2 D3]. The products/intermediates of the pathway can be further modified by the action of CYP27B1. The CYP11A1-derived products are biologically active with functions determined by the lineage of the target cells. This pathway can operate in epidermal keratinocytes. To further define the role of these novel Secosteroids we tested them for protective effects against UVB-induced damage in human epidermal keratinocytes, melanocytes and HaCaT keratinocytes, cultured in vitro . The Secosteroids attenuated ROS, H 2 O 2 and NO production by UVB-irradiated keratinocytes and melanocytes, with an efficacy similar to 1,25(OH) 2 D3, while 25(OH)D3 had lower efficacy. These attenuations were also seen to some extent for the 20(OH)D3 precursor, 20 S -hydroxy-7-dehydrocholesterol. These effects were accompanied by upregulation of genes encoding enzymes responsible for defense against oxidative stress. Using immunofluorescent staining we observed that the Secosteroids reduced the generation cyclobutane pyrimidine dimers in response to UVB and enhanced expression of p53 phosphorylated at Ser-15, but not at Ser-46. Additional evidence for protection against DNA damage in cells exposed to UVB and treated with Secosteroids was provided by the Comet assay where DNA fragmentation was markedly reduced by 20(OH)D3 and 20,23(OH) 2 D3. In conclusion, novel Secosteroids that can be produced by the action of CYP11A1 in epidermal keratinocytes have protective effects against UVB radiation. This article is part of a special issue entitled ‘17th Vitamin D Workshop’.
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correlation between Secosteroid induced vitamin d receptor activity in melanoma cells and computer modeled receptor binding strength
Molecular and Cellular Endocrinology, 2012Co-Authors: Jin Wang, Wei Li, Zorica Janjetovic, Jianjun Chen, Robert C Tuckey, Minh Nguyen, Edith K Y Tang, Duane D Miller, Andrzej SlominskiAbstract:To define the interaction of novel Secosteroids produced by the action of cytochrome P450scc with vitamin D receptor (VDR), we used a human melanoma line overexpressing VDR fused with enhanced green fluorescent protein (EGFP) and tested the ligand induced translocation of VDR from the cytoplasm to the nucleus. Hydroxyderivatives of vitamin D3 with a full length (D3) side chain and hydroxy-Secosteroids with a shortened side chain (pD) stimulated VDR translocation and inhibited proliferation, however, with different potencies. In general the D3 were more potent than pD analogues. Molecular modeling of the binding of the Secosteroids to the VDR genomic binding pocket (G-pocket) correlated well with the experimental data for VDR translocation. In contrast, docking scores for the non-genomic binding site of the VDR were poor. In conclusion, both the length of the side chain and the number and position of hydroxyl groups affect the activation of VDR by novel Secosteroids.
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New vitamin D analogs as potential therapeutics in melanoma.
Expert Review of Anticancer Therapy, 2012Co-Authors: Paulina Szyszka, Michal A. Zmijewski, Andrzej SlominskiAbstract:Extensive evidence shows that the active form of vitamin D3 – 1α,25-dihydroxyvitamin D3 – plays an important role in cancer prevention, has tumorostatic activity and may potentially be used in therapy for melanoma. Vitamin D3 and its analogs (Secosteroids) exert multiple effects on cancer cells, including inhibition of cell growth and induction of differentiation. Activity of Secosteroids depends on multiple cellular factors, including expression of the vitamin D receptor. Despite its endogenous origin, the key drawback for the use of pharmacologically effective doses of 1α,25-dihydroxyvitamin D3 is its hypercalcemic effect leading to profound toxicity. The solution may lie in properties of vitamin D3 analogs with modified side chains, which demonstrate low calcemic activity but conserve the anti-tumor properties. Noncalcemic vitamin D compounds were found to be potent in multiple studies that mandate further clinical testing. Finally, recent studies revealed alternative metabolic pathways for Secosteroid...
Chang-yun Wang - One of the best experts on this subject based on the ideXlab platform.
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Bioactive 9,11‐Secosteroids from Gorgonian Subergorgia suberosa Collected from the South China Sea
ChemInform, 2014Co-Authors: Chang-lun Shao, Min Chen, Jun Qi, Yu Wang, Yu-chun Fang, Chang-yun WangAbstract:isolation, structure and cytotoxicity of five new Secosteroids (I) and seven known analogues
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Subergorgiaols A-L, 9,10-Secosteroids from the South China Sea gorgonian Subergorgia rubra.
Steroids, 2014Co-Authors: Chang-lun Shao, Min Chen, Cai-juan Zheng, Chang-yun WangAbstract:Abstract Twelve new 9,10-Secosteroids designated as subergorgiaols A–L ( 1 – 12 ), along with four known analogues ( 13 – 16 ), were isolated from the gorgonian Subergorgia rubra collected from the South China Sea . Their planar structures and the relative configurations were elucidated by comprehensive spectroscopic methods including NOESY spectra. The absolute configuration of 1 was established by a dimolybdenum tetraacetate [Mo 2 (AcO) 4 ] induced circular dichroism (ICD) procedure and the modified Mosher’s method. Compounds 1 – 12 represent the first series of 9,10-Secosteroids characterized with a hydroxy group at C-8, which are 8-OH derivatives of astrogorgiadiols/calicoferols. Compound 4 exhibited cytotoxicity against the cervical carcinoma cell line (CaSki) with an IC 50 value of 2.4 μM, and 6 showed toxicity toward brine shrimp Artemia salina with an LC 50 value of 2.0 μM.
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Bioactive 9,11‐Secosteroids from Gorgonian Subergorgia suberosa Collected from the South China Sea
Chemistry & Biodiversity, 2014Co-Authors: Chang-lun Shao, Min Chen, Jun Qi, Yu Wang, Yu-chun Fang, Chang-yun WangAbstract:Five new 9,11-Secosteroids 1, 2, and 4–6, and seven known analogs, 3 and 7–12, with the same steroid skeleton, (5αH)-3β,6α,11-trihydroxy-9,11-secocholest-7-en-9-one, were isolated from the South China Sea gorgonian Subergorgia suberosa. Among them, 2/3 and 4/5 are C(24)-epimeric mixtures, and 6/7 is an (E)/(Z) mixture of (C(24)C(28)). Their structures and relative configurations were elucidated by using comprehensive spectroscopic methods including NOESY spectra. The absolute configuration of the steroidal nucleus was established by the modified Mosher method applied to 10 and on the basis of a common biogenesis for all of these compounds. All isolated compounds, 1–12, and five synthetic acetylated derivatives, 12a–12e, were evaluated for their cytotoxicities in vitro. Compounds 4/5, 11, 12, and 12b–12d showed cytotoxic activities against K562 cell line with the IC50 values ranging from 1.09 to 8.12 μM.
Shang-kwei Wang - One of the best experts on this subject based on the ideXlab platform.
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Ubiquitin-Proteasome Modulating Dolabellanes and Secosteroids from Soft Coral Clavularia flava.
Marine Drugs, 2020Co-Authors: Che-yen Chiu, Xue-hua Ling, Shang-kwei WangAbstract: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.
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Secosteroids and Norcembranoids from the Soft Coral Sinularia nanolobata
Marine Drugs, 2013Co-Authors: Yen-ju Tseng, Shang-kwei WangAbstract:Two new 9,11-Secosteroids, 22α-acetoxy-24-methylene-3β,6α,11-trihydroxy-9, 11-seco-cholest-7-en-9-one (1) and 11-acetoxy-24-methylene-1β,3β,6α-trihydroxy-9, 11-seco-cholest-7-en-9-one (2), as well as two known norcembranoids, 5-epi-sinuleptolide (3) and sinuleptolide (4), were isolated from the soft coral Sinularia nanolobata. The structures of these metabolites were elucidated on the basis of extensive spectroscopic analysis. The anti-HCMV (human cytomegalovirus) activity of 1–4 and its cytotoxicity against selected cell lines were evaluated.
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Diterpenoids, norditerpenoids, and Secosteroids from the Formosan soft coral Cespitularia hypotentaculata.
Journal of Natural Products, 2006Co-Authors: Chia-hua Li, Shang-kwei WangAbstract:Four new cespitularane diterpenes, cesputularins I−L (1−4), two new norverticillane norditerpenes, cespitularins M and N (5 and 6), two new verticillane diterpenes, cespitularins O and P (7 and 8), a new norditerpene, cespitularin Q (9) (having a novel carbon skeleton), a new xenicane diterpene, cespitolide (10), and two new Secosteroids, 3β,11-dihydroxy-5β,6β-epoxy-9,11-secocholestan-9-one (11) and 3β,11-dihydroxy-5β,6β-epoxy-9,11-secogorgostan-9-one (12), were isolated from the methylene chloride solubles of the Formosan soft coral Cespitularia hypotentaculata Roxas. The structures were elucidated by extensive spectroscopic analysis, and their cytotoxicity against selected cancer cells was measured in vitro.
Hideo Kigoshi - One of the best experts on this subject based on the ideXlab platform.
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Aplysiasecosterols B and C: two new 9,11-Secosteroids with a cis-fused 1,4-quinone structure from the sea hare Aplysia kurodai
Tetrahedron Letters, 2016Co-Authors: Masaki Kita, Atsushi Kawamura, Hideo KigoshiAbstract:Abstract Two new 9,11-Secosteroids with a cis -fused 3β,5β-dihydroxy-1,4-quinone structure, aplysiasecosterols B and C, were isolated from the sea hare Aplysia kurodai . Their structures were determined by 1D- and 2D-NMR spectroscopic analysis, molecular modeling studies, and a modified Mosher’s method. Aplysiasecosterol B might be the biosynthetic precursor of aplysiasecosterol A, another 9,11-Secosteroid with a tricyclic γ-diketone structure from A. kurodai , via two α-ketol rearrangements and intramolecular acetalization.
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aplysiasecosterol a a 9 11 Secosteroid with an unprecedented tricyclic γ diketone structure from the sea hare aplysia kurodai
Angewandte Chemie, 2015Co-Authors: Atsushi Kawamura, Masaki Kita, Hideo KigoshiAbstract:A new 9,11-Secosteroid having an unprecedented tricyclic γ-diketone structure, aplysiasecosterol A (1), was isolated from the sea hare Aplysia kurodai. The structure was determined by one- and two-dimensional NMR spectroscopic analysis, molecular modeling studies, a comparison of experimental and calculated ECD spectra, and a modified Mosher′s method. Aplysiasecosterol A (1) exhibited cytotoxicity against human myelocytic leukemia HL-60 cells. A biosynthetic pathway for 1 from a known cholesterol was proposed and includes twice α-ketol rearrangements and an intramolecular acetalization.
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Aplysiasecosterol A: A 9,11‐Secosteroid with an Unprecedented Tricyclic γ‐Diketone Structure from the Sea Hare Aplysia kurodai
Angewandte Chemie, 2015Co-Authors: Atsushi Kawamura, Masaki Kita, Hideo KigoshiAbstract:A new 9,11-Secosteroid having an unprecedented tricyclic γ-diketone structure, aplysiasecosterol A (1), was isolated from the sea hare Aplysia kurodai. The structure was determined by one- and two-dimensional NMR spectroscopic analysis, molecular modeling studies, a comparison of experimental and calculated ECD spectra, and a modified Mosher′s method. Aplysiasecosterol A (1) exhibited cytotoxicity against human myelocytic leukemia HL-60 cells. A biosynthetic pathway for 1 from a known cholesterol was proposed and includes twice α-ketol rearrangements and an intramolecular acetalization.