Synthesis and structure–activity relationships of 16-ene-22-thia-1α,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs having side chains of different sizes Original Research Article

We have synthesized eight novel 16-ene-22-thia-26,27-dimethyl-19-norvitamin D3 analogs 1–5 bearing side chains of different sizes, in combination with 20S- and 20R-isomers. The target compounds were prepared by Wittig-Horner reaction of A-ring phosphine oxide with 16-ene-22-thia-25-hydroxy Grundmann’s ketones having different sized side chains, which were derived from the S-phenyloxycarbonyl derivative 13 as key intermediates. The binding affinity to the vitamin D receptor (VDR), VDR-mediated transcriptional activity, and osteoclast-inducing activity of synthetic 22-thia-19-norvitamin D analogs 1–5 were investigated. The (20S)-22-thia-19,24-dinorvitamin D analog 1a is as active as the natural hormone 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2D3) in terms of biological activities tested in vitro. The analogs 2a and 3a exhibited almost the same potency as 1α,25-(OH)2D3 in binding to the VDR, were about 20 times more potent than 1α,25-(OH)2D3 in terms of transcriptional activity, and 3a was approximately 100 times as potent as 1α,25-(OH)2D3 in eliciting osteoclast formation. The biological activities of (20S)-22-thia compounds were more potent (by more than 10-fold) than those of the corresponding 20R-counterparts, but the activity of (20R)-compounds 1b, 2b, and 3b in stimulating the formation of osteoclasts was similar to that of 1α,25-(OH)2D3, and the 24-dihomo- and trihomo-analogs 4a and 5a showed low transcriptional activity. These results suggest that elongation of the side chain in 22-thia analogs by up to one carbon can be stably accommodated in the VDR ligand binding pocket.