title: Antiproliferative Hybrid Analogs of the Hormone 1alpha,25-Dihydroxyvitamin D(3): Design, Synthesis, and Preliminary Biological Evaluation.
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 1alpha,25-dihydroxyvitamin D(3) (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.
authors.affiliation: Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218, and Division of Toxicology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland 21205.
authors.forename: Gary H.
authors.initials: GH
authors.lastname: Posner
authors.forename: Jae Kyoo
authors.initials: JK
authors.lastname: Lee
authors.forename: M. Christina
authors.initials: MC
authors.lastname: White
authors.forename: Richard H.
authors.initials: RH
authors.lastname: Hutchings
authors.forename: Haiyan
authors.initials: H
authors.lastname: Dai
authors.forename: Joseph L.
authors.initials: JL
authors.lastname: Kachinski
authors.forename: Patrick
authors.initials: P
authors.lastname: Dolan
authors.forename: Thomas W.
authors.initials: TW
authors.lastname: Kensler