New Vitamin D3 Derivatives with Unexpected Antiproliferative Activity: 1-(Hydroxymethyl)-25-hydroxyvitamin D3 Homologs

Gary H. Posner, Todd D. Nelson, Kathryn Z. Guyton, Thomas W. Kensler

Research output: Contribution to journalArticle

Abstract

Surprisingly, both of the synthetic 1-(hydroxymethyl)-25-hydroxyvitamin D3 diastereomers (-)-2 and (+)-3 retained the antiproliferative activity of natural calcitriol in murine keratinocytes. Preliminary studies indicated, however, that both of these synthetic diastereomers were less than 0.1% as effective as calcitriol for binding to the 1,25-(OH)2-D3 receptor and that they were less them 0.1% as potent as calcitriol for calbindin-D28K induction in organ-cultured embryonic chick duodenum. 1-(Hydroxymethyl)-25-hydroxyvitamin D3 homologs (-)-2 and (+)-3 were synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketone 12 with highly enantiomerically enriched A-ring phosphine oxides (-)-11a and (+)-11b. These A-ring chirons were prepared starting from thermal [2 + 4] cycloaddition of 3-bromo-2-pyrone and acrolein.

Original languageEnglish (US)
Pages (from-to)3280-3287
Number of pages8
JournalJournal of medicinal chemistry
Volume35
Issue number17
DOIs
StatePublished - Aug 1 1992

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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