Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)- 1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity

Nozomi Saito, Yoshitomo Suhara, Masaaki Kurihara, Toshie Fujishima, Shinobu Honzawa, Hitoshi Takayanagi, Toshiro Kozono, Masahiko Matsumoto, Masayuki Ohmori, Naoki Miyata, Hiroaki Takayama, Atsushi Kittaka

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Abstract

A concise and efficient synthetic approach to 2α-(ω- hydroxyalkoxy)-1α,25-dihydroxyvitamin D3 (4a-c), including 2-epi-ED-71, was developed starting from D-glucose as a chiral template for the construction of the 2α-modified A-ring precursors (11a-c). It was found that the best ligand for the bovine thymus vitamin D receptor (VDR) in this series is 4b, which has 1.8 times greater binding affinity for the bovine thymus VDR than that of the natural hormone 1. Interestingly, potency in the induction of HL-60 cell differentiation for 4a-c was almost the same or weaker than that of 1 despite the strong binding affinity for the VDR. Next, we were interested in the "double modification" of 1 based on 4a-c with C20-epimerization, affording 2α-(ω-hydroxyalkoxy)-20-epi-1α, 25-dihydroxyvitamin D3 (20-epi-4a-c). All three 2α-substituted 20-epi analogues of 1 (20-epi-4a-c) exhibited stronger binding affinities for the VDR, and their conformations in the ligand binding domain of VDR were analyzed by molecular modeling. Double-modified analogues of 20-epi-4a-c showed marked HL-60 cell differentiation activity, and 20-epi-4a possesses an activity 58-fold higher than that of the natural hormone 1.

Original languageEnglish
Pages (from-to)7463-7471
Number of pages9
JournalJournal of Organic Chemistry
Volume69
Issue number22
DOIs
Publication statusPublished - 2004 Oct 29

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ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Saito, N., Suhara, Y., Kurihara, M., Fujishima, T., Honzawa, S., Takayanagi, H., Kozono, T., Matsumoto, M., Ohmori, M., Miyata, N., Takayama, H., & Kittaka, A. (2004). Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)- 1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity. Journal of Organic Chemistry, 69(22), 7463-7471. https://doi.org/10.1021/jo0491051