Synthesis and biological evaluation of novel 6-substituted analogs of 1α,25-dihydroxy-19-norvitamin D3.

We have recently described the synthesis and biological evaluation of 1α,25-dihydroxy-6-methylvitamin D3 which binds the vitamin D receptor (VDR) very effectively. Unfortunately, this compound has a strong tendency to rearrange to its previtamin form. Taking this into consideration, we decided to synthesize a series of 6-substituted analogs of 1α,25-dihydroxy-19-norvitamin D3 which lack the exomethylene moiety at C-10 and thus are unable to undergo a conversion to their respective previtamin forms. The synthesis of analogs bearing different substituents at C-6 was accomplished by Suzuki-Miyaura cross-coupling reaction of a bicyclic organoboron derivative (CD-ring fragment) with the respective alkenyl halides (A-ring synthons). The biological in vitro studies of the affinity of synthesized analogs to the full-length recombinant rat VDR indicate that presence of a bulky, polar substituent at C-6 results in decrease in binding ability. Moreover, introduction of a 6-methyl substituent into the 1α,25-dihydroxy-19-norvitamin D3 molecule results in the 9 times lower affinity of the homolog to the VDR while the same modification of calcitriol has not influenced binding activity. This article is part of a Special Issue entitled 'Vitamin D Workshop'.