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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

Glebocka, A.; Sokolowska, K.; Sicinski, R.R.; Plum, L.A.; Deluca, H.F.

Journal of Medicinal Chemistry 52(11): 3496-3504

2009

ISSN/ISBN: 1520-4804
PMID: 19402630
DOI: 10.1021/jm9001583
Accession: 054596121
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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.

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