Synthesis and biological evaluation of (23R)- and (23S)-24,24-difluoro-1 alpha,23,25-trihydroxyvitamin D3.
The syntheses and biological evaluations of (23R)- and (23S)-24,24-difluoro-1 alpha,23,25-trithydroxyvitamin D3 (3a and 3b), new C-24 fluorinated analogs of 1 alpha,25-dihydroxyvitamin D3, are described. The syntheses of these compounds were achieved in 3 steps from (5Z,7E,20R)-1 alpha,3 beta-bis-[(tert-butyldimethylsilyl)oxy]-20-formylmethyl-9,10-seco- 5,7,10(19) pregnatriene (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 1 alpha,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.
Iwasaki
H
H
Tsukuba Research Laboratory, NOF Corporation, Ibaraki, Japan.
Miyamoto
Y
Y
Hosotani
R
R
Nakano
Y
Y
Konno
K
K
Takayama
H
H
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004341:Drug Evaluation; D018922:HL-60 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley
C117122:24,24-difluoro-1,23,25-trihydroxyvitamin D3; D002117:Calcitriol