Biological activity and conformational analysis of C20 and C14 epimers of CD-ring modified trans-decalin 1alpha,25-dihydroxyvitamin D analogs.
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.
De Clercq
Pierre J
PJ
Laboratory for Organic Synthesis, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Gent, Belgium. pierre.declercq@UGent.be
Murad
Ibrahim
I
Gao
Ling-Jie
LJ
Chen
Yong-Jun
YJ
Van Haver
Dirk
D
Vandewalle
Maurits
M
Verstuyf
Annemieke
A
Verlinden
Lieve
L
Verboven
Christel
C
Bouillon
Roger
R
D000818:Animals; D002117:Calcitriol / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D013057:Spectrum Analysis
D002117:Calcitriol