Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3.
The activated vitamin D3 derivative 26,27-F6-1alpha,25(OH)2D3 (2a), its three A-ring diastereomers (2b, 2c, 2d), and 5,6-trans isomer (2e) were prepared. Two analogues (2b, 2c) of these isomers were synthesized by a palladium catalyzed coupling reaction using vinyl bromide 5 and enynes (6a, 6b), which were derived from readily commercially available 2S-(+)-glycidyl p-toluenesulfonate 7, as a common starting material. Competitive vitamin D receptor (VDR) binding affinities of these diastereomers of 2a were evaluated. Interestingly, the stereochemical effects at C-1,3 of 2a were considerably more moderate than those of 1alpha,25(OH)2D3 (1). In particular, isomerization at the 5,6-double bond of 2a only slightly reduced VDR affinity, whereas 5,6-trans-1alpha,25(OH)2D3 had a significantly lower binding affinity than 1.
Ikeda
M
M
Sumitomo Pharmaceuticals Research Center, Osaka, Japan. ikeda@sumitomopharm.co.jp
Takahashi
K
K
Dan
A
A
Koyama
K
K
Kubota
K
K
Tanaka
T
T
Hayashi
M
M
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002645:Chickens; D007700:Kinetics; D015394:Molecular Structure; D011869:Radioligand Assay; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013237:Stereoisomerism; D005466:Fluorocarbons
D002117:Calcitriol; D018167:Receptors, Calcitriol; C040488:26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3; D005466:Fluorocarbons