Synthesis and Biological Evaluation of (23R)- and (23S)-24, 24-Difluoro-1α, 23, 25-trihydroxyvitamin D₃

Abstract

The syntheses and biological evaluations of (23R)- and (23S)-24, 24-difluoro-1α, 23, 25-trithydroxyvitamin D₃ (3a and 3b), new C-24 fluorinated analogs of 1α, 25-dihydroxyvitamin D₃, are described. The syntheses of these compounds were achieved in 3 steps from (5Z, 7E, 20R)-1α, 3β-bis-[(tert-butyldimethylsilyl)oxy]-20-formylmethyl-9, 10-seco-5, 7, 10(19)oregnatriene (5) which is derived from vitamin D₂. The absolute configuration at the C-23 position of 3a and 3b was determined by the modified Mosher method. The relative affinities of 3a and 3b to the vitamin D receptor were both 10 and 14 times lower than that of 1α, 25-dihydroxyvitamin D₃ (1), and to vitamin D binding protein were also both 130 and 40 times lower. The HL-60 cell differentiating activity of 3a was 6 times more potent than that of 1, while there was no remarkable difference in activity between 3b and 1.