1993 Fiscal Year Final Research Report Summary
Studies on the synthesis, conformational analysis, and biological activity of active vitamin D analogs in the purpose of developing therapeutic agent with selective activity
| Project/Area Number |
04671289
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
YMADA Sachiko Tokyo Med. Dental Univ. Inst. Med. Dental Eng. Professor, 医用器材研究所, 教授 (10014078)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Keiko Tokyo Med. Dental Univ. Inst. Med. Dental Eng. Research Associate, 医用研, 助手 (90147017)
SHIMIZU Masato Tokyo Med. Dental Univ. Inst. Med. Dental Eng. Associate Professor, 医用研, 助教授 (50126231)
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| Project Period (FY) |
1992 – 1993
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| Keywords | vitamin D / analog / synthesis / conformational analysis / structure activity relationship / conjugate addition / receptor / vitamin D binding protein |
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| Research Abstract |
(1) Syntheses and biological activity of active vitamin D_3 side chain analogs :
Active vitamin D_3 analogs alkylated at the 22-position were designed and synthesized to study the stereochemical structures required to bind to the receptor (VDR) for the active vitamin D_3 and to serum vitamin D binding protein (DBP). (22R)-and(22S)-Methylated analogs were synthesized via kinetically controlled conjugate addition of Me_2CuLi to (22E)-and (22Z)-22-en-24-one as the key step. Only the 22S-methyl analog mimicked the activities of the active vitamin D_3. The results suggest that the side chain conformation of the active viramin D_3 best fitted to VDR and DBP is the same 17-20-22-23 anti form. Additional eight 22-substituted active vitamin D analogs who are diastereomers at C(20) and C(22) were synthesized by using the same synthetic strategy. Conformational analysis and biological activity of these analogs provided an insight into the spatial arrangement of vitamin D side chain esponsible for the activities.
(2) Syntheses and biological activity of 1-substituted active vitamin D_3 analogs :
To study the A-ring conformation responsible for the activity of the active vitamin D_3, various 1beta-substituted 1alpha, 25-dihydroxyvitamin D_3 derivatives were synthesized via two routes. In the method 1, synthesis was started with readily available C(22)-steroid. The method 2 used 1-oxoprevitamin D as the starting material which gave predominantly (64%) 1beta-R-1alpha-hydroxy previtamin D on treatment with RLi. Interestignly the introduction of a methyl group at the 1beta-position masked almost completely the action of 1-alpha hydroxyl group.
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[Publications] Yamamoto, K. ; Shimizu, M. ; Yamada, S. ; Iwata, S. ; Hoshino, O.: "Facile Stereoselective Synthesis of (23S,25R)-1alpha, 25-Dihydroxyvitamin D_3 26,23-Lactone, A Major Metabolite of 1alpha, 25-Disydroxyvitamin D_3." J.Org.Chem.57. 33-39 (1992)
Description
「研究成果報告書概要(欧文)」より
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