Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D₃ Derivatives: Stereoselectivity and Biological Activity

The active form of vitamin D₃ (D₃), 1a,25-dihydroxyvitamn D₃ (1,25D₃), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D₃ have been conducted, with the aim of separating the biological activities of 1,25D₃ or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D₃ derivatives with alkoxy groups at C2, by means of the Julia-Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted C2α-7a was found to show potent cell-differentiating activity, with an ED₅₀ value of 0.38 nM, being 26-fold more potent than 1,25D₃.