Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1α,25-dihydroxyvitamin D3: Synthesis and biological evaluation

G. H. Posner, K. Crawford, M. L. Siu-Caldera, G. S. Reddy, S. F. Sarabia, D. Feldman, E. Van Etten, C. Mathieu, L. Gennaro, P. Vouros, S. Peleg, P. M. Dolan, T. W. Kensler

Research output: Contribution to journalArticle

Abstract

New C,D-ring side-chain-modified sulfone 4a, with natural 1α,3β-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1α,25-dihydroxyvitamin D3 (1), has been prepared and characterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermediate and (2) smooth reductive etherification without interference by a neighboring sulfonyl group. Sulfone 4a, but not its 1β,3α-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resemble Leo Pharmaceutical. Co.'s KH-1060 (3), is recognized by catabolic enzymes, the selective biological profile of sulfone 4a is likely not due to its metabolites that are formed in only minor amounts.

Original languageEnglish (US)
Pages (from-to)3581-3586
Number of pages6
JournalJournal of medicinal chemistry
Volume43
Issue number19
DOIs
StatePublished - Sep 21 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Posner, G. H., Crawford, K., Siu-Caldera, M. L., Reddy, G. S., Sarabia, S. F., Feldman, D., Van Etten, E., Mathieu, C., Gennaro, L., Vouros, P., Peleg, S., Dolan, P. M., & Kensler, T. W. (2000). Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1α,25-dihydroxyvitamin D3: Synthesis and biological evaluation. Journal of medicinal chemistry, 43(19), 3581-3586. https://doi.org/10.1021/jm000215j