Biological activity and conformational analysis of C20 and C14 epimers of CD-ring modified trans-decalin 1alpha,25-dihydroxyvitamin D analogs

The Journal of Steroid Biochemistry and Molecular Biology
P J De ClercqRoger Bouillon

Abstract

In the context of our ongoing study of vitamin D structure-function relationships and in an attempt to obtain a better dissociation of their prodifferentiating (HL-60) and/or antiproliferative (MCF-7) activities and their calcemic activity, further 20-epi and 14-epi modifications were made to three trans-decalin CD-ring analogs of 1,25-dihydroxyvitamin D(3), the hormonally active metabolite of vitamin D(3), possessing a natural 20R side chain and featuring additional structural modifications in the seco-B-ring and in the A-ring. Following a previously observed trend and in agreement with the conformational analysis results, all three 20-epi derivatives show substantially lower biological activities, opposite to what is usually observed for analogs having the natural CD-ring. The 14-epi modification (cis-decalins) has little effect on the biological activity of the ynediene type and the saturated derivative, but results in an approximate 10-fold reduction in activity of the previtamin derivative. No better dissociation of the prodifferentiating and/or antiproliferative activities and the calcemic activity was achieved.

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Citations

Jun 23, 2005·Diabetologia·C MathieuR Bouillon
Jan 16, 2007·The Journal of Steroid Biochemistry and Molecular Biology·Pierre J De ClercqRoger Bouillon
Dec 11, 2007·European Journal of Medicinal Chemistry·Maykel Pérez GonzálezGenerosa Gómez
Feb 3, 2006·Natural Product Reports·James R Hanson

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