A non-calcemic sulfone version of the vitamin D3 analogue seocalcitol (EB 1089): chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin

Gary H. Posner, Kenneth R. Crawford, Sara Peleg, Jo Ellen Welsh, Saara Romu, David A. Gewirtz, Mona S. Gupta, Patrick Dolan, Thomas W. Kensler

Research output: Contribution to journalArticle

Abstract

Novel side-chain diene sulfones 5, analogues of the natural hormone 1α 25-dihydroxyvitamin D3 (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Companys drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9→10) and Horner Wadsworth Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1α,3b-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 mg/kg of rat body weight.

Original languageEnglish (US)
Pages (from-to)2365-2371
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume9
Issue number9
DOIs
StatePublished - Sep 26 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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