Studies on the synthesis, conformational analysis, and biological activity of active vitamin D analogs in the purpose of developing therapeutic agent with selective activity

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(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.