Antiproliferative hybrid analogs of the hormone 1α,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation

G. H. Posner, J. K. Lee, M. C. White, R. H. Hutchings, H. Dai, J. L. Kachinski, P. Dolan, T. W. Kensler

Research output: Contribution to journalArticlepeer-review

Abstract

The combination of 10-12 kbar pressure plus Lewis acidic zinc dichloride promotes highly regioselective and stereoselective Diels-Alder cycloaddition between 3-bromo-2-pyrone, prepared in a new way, and unactivated terminal alkene 4-(tert-butyldimethylsiloxy)-1-butene. The conjugate base of A-ring allylic phosphine oxide 20 adds chemospecifically to the C-8 keto group of some C-8,C-24-diketones to form directly metabolically resistant 24-oxo analogs of 1α,25-dihydroxyvitamin D3 (calcitriol). Several of these new hybrid analogs are as efficacious in vitro as calcitriol at inhibiting growth of murine keratinocytes even at physiologically relevant 10-100 nanomolar concentrations.

Original languageEnglish (US)
Pages (from-to)3299-3314
Number of pages16
JournalJournal of Organic Chemistry
Volume62
Issue number10
DOIs
StatePublished - Jan 1 1997

ASJC Scopus subject areas

  • Organic Chemistry

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