Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Glebocka A,Sokolowska K,Sicinski RR,Plum LA,Deluca HFdoi
10.1021/jm9001583subject
Has Abstractpub_date
2009-06-11 00:00:00pages
3496-504issue
11eissn
0022-2623issn
1520-4804journal_volume
52pub_type
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