ANTIPROLIFERATIVE HYBRID ANALOGS OF THE HORMONE 1-ALPHA,25-DIHYDROXYVITAMIN D-3 - DESIGN, SYNTHESIS, AND PRELIMINARY BIOLOGICAL EVALUATION

The combination of 10-12 kbar pressure plus Lewis acidic zinc dichlori de promotes highly regioselective and stereoselective Diels-Alder cycl oaddition between 3-bromo-2-pyrone, prepared in a new way, and unactiv ated terminal alkene 4-(tert-butyldimethylsiloxy)-1-butene. The conjug ate base of A-ring allylic phosphine oxide 20 adds chemospecifically t o the C-8 keto group of some C-8,C-24-diketones to form directly metab olically resistant 24-oxo analogs of 1 alpha 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.