Antiproliferative Hybrid Analogs of the Hormone 1alpha,25-Dihydroxyvitamin D(3): Design, Synthesis, and Preliminary Biological Evaluation.
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.
Posner
Gary H.
GH
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.
Lee
Jae Kyoo
JK
White
M. Christina
MC
Hutchings
Richard H.
RH
Dai
Haiyan
H
Kachinski
Joseph L.
JL
Dolan
Patrick
P
Kensler
Thomas W.
TW