2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation, and crystal structure.

Recently, we have found that 16-ene-22-thia-26,27-dimethyl-19-norvitamin D(3) analogs 1a (n=2, 3) are 20 times more active than the natural hormone 1alpha,25-dihydroxyvitamin D(3) in terms of transcriptional activity. To further investigate the effects of the A-ring modification of 1a, b on the biological activity profile, novel 22-thia-19-norvitamin D analogs 2-11 bearing a hydroxyethoxy-, hydroxyethylidene- or methyl group at C-2 in combination with 20S- and 20R-isomers were prepared and tested for their in vitro biological activities. All of the synthesized analogs showed 0.

Synthesis and structure-activity relationships of 16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs having side chains of different sizes.

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.