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

The active form of vitamin D-3 (D-3), 1a,25-dihydroxyvitamn D-3 (1,25D(3)), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D-3 have been conducted, with the aim of separating the biological activities of 1,25D(3) 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 1,25D(3) 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 C2 alpha-7a was found to show potent cell-differentiating activity, with an ED50 value of 0.38 nM, being 26-fold more potent than 1,25D(3).