Convergent synthesis, chiral HPLC, and vitamin D receptor affinity of analogs of 1,25-dihydroxycholecalciferol

A series of analogs of 1,25-dihydroxycholecalciferol was obtained with an a dditional chiral center at the terminus of the aliphatic side chain (C-25). The analogs were obtained from (+)-(R)- and (-)-(S)-2-methylglycidols, by opening of the oxirane ring with the carbanions derived from vitamin D C-23 a,C-24- or C-22-sulfones. The diastereomeric purity of the analogs was dete rmined by high-performance liquid chromatography on a chiral stationary pha se. The binding affinity of analogs for the calf thymus intracellular vitam in D receptor (VDR) was two orders of magnitude lower than that of the lead compound of this group, 24a,24b-dihomo-1,25-dihydroxycholecalciferol, and it was comparable to the affinity of analogs of 24-nor-1,25-dihydroxycholec alciferol. However, a twofold difference was observed for analogs diastereo meric at C-25 in their affinity for VDR The diastereodifferentiation of the binding affinity was found to be specific for vitamin D vicinal 25,26-diol s as it disappears for analogs where 26-hydroxyl, neighboring the C-25 chir al center, is replaced with methyl. Chirality 11:249-255, 1999. (C) 1999 Wi ley-Liss, Inc.