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
[...] Read more.
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
C2α-7a was found to show potent cell-differentiating activity, with an ED
50 value of 0.38 nM, being 26-fold more potent than 1,25D
3.
Full article
