著者

山本 恵子 崔 美花 増野 弘幸 山田 幸子

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 43 (ISSN:24331856)

巻号頁・発行日

pp.73-78, 2001-09-01 (Released:2017-08-18)

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Conformational analysis of the side chain of 1α,25-dihydroxyvitamin D_3 [1,25-(OH)_2D_3, 1] and its 20-epimer 2 revealed that the spatial region occupied by the side chain of these vitamin Ds can be divided to four areas. We designed and synthesized four diastereomers 3-6 at C(20) and C(22) of 22-methyl-1,25-(OH)_2D_3 whose side-chain mobility is restricted in one of these four areas. We tested biological activities of these four analogs. These studies allowed us to propose the relationship between the spatial region of the vitamin D side-chain and the activity, an active space group concept. This concept has been generally accepted as explaining the three-dimensional structure and activity relationship of almost all known vitamin D analogs. We constructed the three-dimensional structure of the ligand binding domain (LBD) of vitamin D receptor (VDR) based on the crystal structure of retinoic acid receptor by the homology modeling technique. We docked 1,25-(OH)_2D_3 1 as a ligand into the constructed VDR-LBD. Three residues forming the hydrogen bonds with the functionally important 1α- and 25-hydroxyl groups of 1 were identified and confirmed by the mutational analysis: the 1α-hydroxyl group is forming pincer type hydrogen bonds with S237 and R274 and the 25-hydroxyl group is interacting with H397. By the computational docking studies based on the mutational analysis of the VDR, we obtained the docking models of the VDR with the functionally and structurally interesting ligands. From these studies we suggested key structural factors to bestow the augmented activities on 20-epi-vitamin Ds.

著者

我妻 勉 赤間 勉 奈良 真二 中井 龍一郎 小川 はる美 斎藤 裕 池田 俊一 松宮 茂樹 大瀧 静夫 神田 裕

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 43 (ISSN:24331856)

巻号頁・発行日

pp.431-436, 2001-09-01 (Released:2017-08-18)

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In the course of our search for new antitumor agents from microorganisms, the fungus Acremonium sp. KY4917 was found to produce novel compounds. Two novel compounds, UCS1025A (1) and B (2), were isolated from the culture broth by chromatographic methods. Molecular formulae of 1 and 2 were determined to be C_<20>H_<25>NO_5 and C_<20>H_<25>NO_6 from HRFAB-MS data, respectively. Structures of 1 and 2 were elucidated on the basis of spectroscopic methods, mainly by detailed analyses of their NMR spectra. Absolute stereochemistry of 1 was established by an X-ray crystallographic analysis of the 3'-bromo derivative 3'. As a result of spectroscopic analyses and chemical transformations of 1, the unique chemical equilibrium of 1 was found out. Three tautomeric isomers of 1 have been identified to be ketone 1a in CDCl_3 by NMR analyses, enol 1b by an X-ray crystallographic analysis, and enedione 1c in an aqueous buffered solution, respectively. UCS1025A (1) exhibited antimicrobial activity against Gram-positive bacteria, Staphylococcus anreus, Bacillus subtilis and Enterococcus hirae, and Gram-negative bacterium, Proteus vulgaris with the MIC values ranged from 1.3μg/mL to 5.2 μg/mL, and antiproliferative activity against human tumor cell lines (A431 and MCF-7) with the IC_<50> values 55 μM and 21 μM, respectively. In contrast, UCS1025B (2) showed weak antimicrobial and no antiproliferative activity.