STUDIES ON THE SYNTHESIS AND METABOLISM OF 14-epi-2α-(3-HYDROXYPROPYL)-19-NORVITAMIN D3 AND ITS 2β-ISOMER

Two derivatives of 14-epi-1 alpha,25-Dihydroxy-19-norvitamin D-3, 14-epi-2 alpha-(3-hydroxypropyl)-1 alpha,25-dihydroxy-19-norvitamin D-3 (14-epi-MART-10) and its 2-epimeric analog (14-epi-MART-11), were synthesized using Julia coupling reaction to connect between the C5 position (steroidal numbering) of an A-ring precursor ketone derived from (-)-quinic acid and the C6 position of a protected 14-epi-CD-ring benzothiazole sulfone. The coupling and deprotection reactions generated a mixture of 14-epi-MART-10 and 14-epi-MART-11 in a moderate yield. The C2-isomers were then separated as their pivalate forms. The C2-stereochemistry of 2 alpha- and 2 beta-isomers was determined by H-1 NMR studies including NOE experiments. The pivaloyl group was removed under basic conditions to obtain the target molecules of 14-epi-MART-10 and 14-epi-MART-11. The metabolism of these two new analogs was further studied in a reconstituted cell-free human CYP24A1 system to elucidate the potential mechanism of their super agonistic action on vitamin D receptor. Our results indicate that epimerization at C14 makes the analogs less susceptible to CYP24A1 degradation and therefore more bio-available, leading to enhanced biological activities.