A 20S Combined with a 22R Configuration Markedly Increases both in vivo and in vitro Biological Activity of 1α25-Dihydroxy-22-methyl-2-methylene-19-norvitamin D3

摘要

Six new analogues of 1α,25-dihydroxy-19-norvitamin D3 (>3a-4b, 5 and >6) were prepared by a convergent synthesis applying the Wittig-Horner reaction as a key step. The influence of methyl groups at C-22 on their biological activity was examined. It was established that both in vitro and in vivo activity is strongly dependent on the configuration of the stereogenic centers at C-20 and C-22. Introduction of the second methyl group at C-22 (analogues >5 and >6) generates the compounds that are slightly more potent than 1α,25-(OH)2D3 in the in vitro tests but much less potent in vivo. The greatest in vitro and in vivo biological activity was achieved when the C-20 is in the S-configuration and the C-22 is in the R configuration. The building blocks for the synthesis, the respective (20R,22R)-, (20R,22S)-, (20S,22R)- and (20S,22S)-diols were obtained by fractional crystallization of mixtures of the corresponding diastereomers. Structures and absolute configurations of the diols >21a, 21b and >22a as well as analogues >3a, 5 and >6 were confirmed by the X-ray crystallography.