Synthesis and biologic activity of a C-ring analogue of vitamin D3: biologic and protein binding properties of 11 alpha-hydroxyvitamin D3.
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-3 beta-ol (1) to the 5,7,9(11)-triene. After protection of the 5,7-diene with a 4-phenyl-1,2,4- 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-3 beta, 11 alpha-diol (6). Photolysis of 6 to the previtamin followed by thermal rearrangement resulted in 11 alpha-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 X 10(-8) M) than 25-hydroxyvitamin D3, 24(R),25-dihydroxyvitamin D3, and 25-(S), 26-dihydroxyvitamin D3 (7.1 X 10(-9) M, 7.7 X 10(-9) M, and 7.9 X 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 1 alpha-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and vitamin D3 (B-50 = 2.5 X 10(-6) M, 9.84 X 10(-8) M, and 5.46 X 10(-7) M, respectively), under these same conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002645:Chickens; D006887:Hydroxycholecalciferols / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects; D008297:Male; D051381:Rats; D013329:Structure-Activity Relationship; D014809:Vitamin D-Binding Protein
D002352:Carrier Proteins; D006887:Hydroxycholecalciferols; D014809:Vitamin D-Binding Protein; C041625:11-hydroxyvitamin D3; D002118:Calcium