New 1alpha,25-dihydroxy-19-norvitamin D(3) compounds constrained in a single A-ring conformation: synthesis of the analogues by ring-closing metathesis route and their biological evaluation.
Vitamin D compounds possessing A rings prohibited from flipping to the alternative chair form (i.e., analogues 2 and 26) were synthesized. The bicyclic fragment 22 consisting of the fused cyclohexane and dihydropyran rings was constructed via the ring-closing metathesis route. Also, a homologous synthon 23 with an attached dihydropyran ring was successfully synthesized using this strategy. The carbonyl deprotection in 22 yielded cyclohexanone 5 that was subjected to Julia coupling with the anion of the phenylthiazoline sulfone 25. In the resulting isomeric 19-norvitamins 2 and 26, their A rings can exist only in the alpha- and beta-conformation. The analogue 26 was 300 times more active in binding to the vitamin D receptor protein, 30 times more effective in causing HL-60 differentiation, and 10 times more active in transcription. These results confirm that the beta-chair form of the vitamin D ring A is necessary for the binding to the receptor.
Glebocka
Agnieszka
A
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Sokolowska
Katarzyna
K
Sicinski
Rafal R
RR
Plum
Lori A
LA
Deluca
Hector F
HF
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D009654:Norsteroids / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014808:Vitamin D Deficiency / Q000188:drug therapy
D009654:Norsteroids; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium