Design, synthesis, and biological evaluation of a 1α,25-dihydroxy-19-norvitamin D3 analogue with a frozen a-ring conformation

To establish the conformation of vitamin D compounds responsible for biological activity, a 1 alpha,25-dihydroxy-19-norvitamin D analogue 4 possessing a 1 alpha-hydroxy group fixed in the axial orientation (beta-chair form) was synthesized. The starting compounds were bicyclic lactones 6, 7a, and 7b, derived from the quinic acid lactone, which were converted to the bicyclic ketone 13. Julia coupling of this compound with sulfone 15 produced the 19-norvitamin D analogue 4, possessing an additional ring connecting the 3 beta-oxygen and C-2, and the isomeric 3 beta-hydroxy compound 5. In vitro, both analogues 4 and 5 exhibit reduced activity compared to the natural hormone 1, but the binding, differentiation, and transcriptional activities of analogue 5 are markedly higher than that of 4 constrained in the (x-chair conformation. Surprisingly, in vivo tests in mice showed that the analogue 4 significantly increases serum calcium at dose levels simiiar to 1 alpha,25-(OH)(2)D-3. These seemingly discordant results are discussed.