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, Thomas W Kensler

Research output: Contribution to journalArticle

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 - 1997

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Calcitriol
phosphine
Hormones
Cycloaddition
Alkenes
Oxides
Zinc

ASJC Scopus subject areas

  • Organic Chemistry

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Antiproliferative hybrid analogs of the hormone 1α,25-dihydroxyvitamin D3 : Design, synthesis, and preliminary biological evaluation. / Posner, G. H.; Lee, J. K.; White, M. C.; Hutchings, R. H.; Dai, H.; Kachinski, J. L.; Dolan, P.; Kensler, Thomas W.

In: Journal of Organic Chemistry, Vol. 62, No. 10, 1997, p. 3299-3314.

Research output: Contribution to journalArticle

Posner, G. H. ; Lee, J. K. ; White, M. C. ; Hutchings, R. H. ; Dai, H. ; Kachinski, J. L. ; Dolan, P. ; Kensler, Thomas W. / Antiproliferative hybrid analogs of the hormone 1α,25-dihydroxyvitamin D3 : Design, synthesis, and preliminary biological evaluation. In: Journal of Organic Chemistry. 1997 ; Vol. 62, No. 10. pp. 3299-3314.
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AU - Lee, J. K.

AU - White, M. C.

AU - Hutchings, R. H.

AU - Dai, H.

AU - Kachinski, J. L.

AU - Dolan, P.

AU - Kensler, Thomas W

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