Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1α,25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation

Gary H. Posner, Jae Kyoo Lee, Qiang Wang, Sara Peleg, Martin Burke, Henry Brem, Patrick Dolan, Thomas W. Kensler

Research output: Contribution to journalArticle

Abstract

Four new hybrid analogues of 1α,25-dihydroxyvitamim D3 (1) have been synthesized in a convergent manner by joining A-ring and C,D-ring fragments. Each hybrid analogue, having a noncalcemic 1-hydroxymethyl group and a potentiating 16-ene 24,24-difluorinated C,D-ring side chain, was designed to be lipophilic and inert toward 24-hydroxylase enzyme catabolism. Each hybrid analogue with lβ,3α-substituent stereochemistry (i.e., analogues 3b and 4b) showed a pharmacologically desirable combination of in vitro high antiproliferative activity in two different cell lines and high transcriptional activity with also low calcemic activity in vivo.

Original languageEnglish (US)
Pages (from-to)3008-3014
Number of pages7
JournalJournal of Medicinal Chemistry
Volume41
Issue number16
DOIs
StatePublished - Jul 30 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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