Synthesis and biologic activity of a C-ring analogue of vitamin D3: Biologic and protein binding properties of 11α-hydroxyvitamin D3

Larry Revelle, Vishnu Solan, James Londowski, Susan Bollman, Rajiv Kumar

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

The influence of C-ring substituents on the biologic activity and protein binding properties of vitamin D3 has not been systematically investigated. To this end, we dehydrogenated cholesta-5,7-dien-3β-ol (1) to the 5,7,9(11)-triene (3). After protection of the 5,7-diene with a 4-phenyl-l,2,4-triazoline-3,5-dione Diels-Alder adduct, oxidation of the unprotected 9(11)-olefin gave epoxide 5. Reverse Diels-Alder and reductive ring opening of epoxide 5 gave cholesta-5,7-diene-3β,11α-diol (6). Photolysis of 6 to the previtamin followed by thermal rearrangement resulted in 11α-hydroxyvitamin D3 (8). We found that vitamin 8 increased calcium transport at a dose of 500 pmol/rat but failed to increase bone calcium mobilization at a dose as high as 50 000 pmol/rat. Under the same conditions, corresponding doses of vitamin D3 and 25-hydroxyvitamin D3 increased bone calcium mobilization and intestinal calcium transport. The new vitamin analogue, 8, was slightly less efficient (B-50 = 6.8 × 10-8 M) than 25-hydroxyvitamin D3, 24(R),25-dihydroxyvitamin D3, and 25-(S),26-dihydroxyvitamin D3 (7.1 × 10-9 M, 7.7 × 10-9 M, and 7.9 × 10-9 M, respectively) in displacing radiolabeled 25-hydroxyvitamin D3 from rat plasma vitamin D binding protein. On the other hand, vitamin analogue 8 showed significantly greater binding efficiency than 1α-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and vitamin D3 (B-50 = 2.5 × 10-6 M, 9.84 × 10-8 M, and 5.46 × 10-7 M, respectively), under these same conditions. Vitamin analogue 8 displayed approximately the same efficiency as vitamin D3 in displacing radiolabeled 1,25-dihydroxyvitamin D3 from a chick intestinal cytosol receptor but was less effective than 25-hydroxyvitamin D3, 24-(R),25-dihydroxyvitamin D3, 25(S),26-dihydroxyvitamin D3, 1α-hydroxyvitamin D3, and 1,25-dihydroxyvitamin D3. We conclude that introduction of an 11α-hydroxyl group into the C-ring of vitamin D3 results in a vitamin analogue with moderate vitamin D3 agonist activity in the intestine but no activity with respect to bone calcium mobilization at the levels tested. 11α-Hydroxyvitamin D3 does not have improved binding affinity to the intestinal cytosol receptor when compared to vitamin D3. The new vitamin analogue shows significantly greater binding affinity to plasma vitamin D binding protein than vitamin D3 (6.79 × 10-8 M vs. 5.46 × 10-7 M) or 1α-hydroxyvitamin D3 (6.79 × 10-8 M vs. 2.5 × 10-6 M), suggesting that the presence of an extra hydroxyl group sufficiently removed from the 3β-hydroxyl is important in the binding of vitamin D analogues to vitamin D binding protein.

Original languageEnglish (US)
Pages (from-to)1983-1987
Number of pages5
JournalBiochemistry
Volume23
Issue number9
StatePublished - 1984

ASJC Scopus subject areas

  • Biochemistry

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