Biological evaluation of epoxy analogs of 1α,25-dihydroxyvitamin D 3

Abstract

The biological activity of 16-epoxy side-chain analogs of 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2D 3) was evaluated in vitro and in vivo. Compared to 1α,25(OH) 2D 3, all analogs had lower affinities for the pig duodenal vitamin D receptor and also for the human serum vitamin D binding protein. The in vitro effects on cell proliferation or differentiation of human promyeloid leukemia (induction of superoxide production in HL-60 cells), human osteosarcoma MG-63 cells (osteocalcin secretion), or human breast cancer cells (incorporation of thymidine in MCF-7 cells), was markedly inhibited by several epoxy analogs, compared to 1α,25(OH) 2D 3, but the rank order of their activity widely varied among different cancer cells. The most potent analogs (24 S,25 S-24-hydroxy-25,26-epoxy-22-ene-1α-OHD 3), 25,26-epoxy-23-yne-1α-OHD 3 and 25,26-epoxy-23-yne-20-epi-1α-OHD 3 or compounds 16, 5, and 7, respectively) were equipotent ( 16 and 5) or 30-fold (compound 7 on MG-63 cells) to 40-fold (compound 7 on MCF-7 cells) more active than 1α,25-(OH) 2D 3. These analogs were nevertheless poorly antirachitic (<3%) when tested in vitamin D-deficient chicks (using serum and bone calcium, serum osteocalcin and duodenal calbindin D-28K, as end points). Compound 7 was also 100-fold more active than 1α,25-(OH) 2D 3 in inhibition of proliferation of human foreskin keratinocytes. Some epoxy analogs of 1α,25-(OH) 2D 3 thus display interesting dissociations between their receptor affinity and their potency to induce cell differentiation, whereas their effect on cell proliferation/differentiation exceed their calcemic effects more than 100- to 1000-fold.