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Paper | Special issue | Vol 82, No. 1, 2010, pp.649-661
Published online, 1st July, 2010
DOI: 10.3987/COM-10-S(E)40
Studies on the Synthesis and Metabolism of 14-epi-2α-(3-Hydroxypropyl)-19-norvitamin D3 and Its 2β-Isomer

Atsushi Kittaka,* Hideki Hara, Kaori Yasuda, Masashi Takano, Midori A. Arai, Daisuke Sawada, Hiroshi Saito, Kazuya Takenouchi, Tai C. Chen, and Toshiyuki Sakaki*

*Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Midori-ku, Sagamihara-shi, Kanagawa 252-5195, Japan

Abstract

Two derivatives of 14-epi-1α,25-Dihydroxy-19-norvitamin D3, 14-epi-2α-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3 (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 2α- and 2β-isomers was determined by 1H 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.