New derivatives of 1α,25-dihydroxy-19-norvitamin D3 with two substituents at C-2: synthesis and biological activity

To examine the effect of 2,2-disubstitution on the biological activities of 19-norvitamin D analogs, novel 2,2-disubstituted-(20R)- and (20S)-1α,25-dihydroxy-19-norvitamin D3 analogs were prepared and their biological activities were studied. All the synthesized analogs possessing hydrophobic 2α-substituents were more active than the corresponding 2β-isomers both in binding to the vitamin D receptor and in activating gene transcription. The 2α-methyl-2β-hydroxy analog 9b was found to have markedly higher transcriptional activity (32-fold) than the natural ligand 1a, although the two had the same binding affinity to the vitamin D receptor. To our knowledge, this analog is among the most potent of 19-norvitamin D analogs.