Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 20, Pages 8319-8331Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm500750b
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Funding
- Wisconsin Alumni Research Foundation
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The 20R- and 20S-isomers of 25-hydroxy-2-methylene-vitamin D-3 and 3-desoxy-1 alpha,25-dihydroxy-2-methylene-vitamin D-3 have been synthesized. Two alternative synthetic routes were devised for preparation of the required A-ring synthons, starting from the chiral compound derived from the (-)-quinic acid and, alternatively, from the commercially available achiral precursor, monoprotected 1,4-cyclohexanedione. The A-ring dienynes were coupled by the Sonogashira process with the respective C,D-ring fragments, the enol triflates derived from the protected (20R)- or (20S)-25-hydroxy Grundmann ketones. All four compounds possessed significant in vivo activity on bone calcium mobilization and intestinal calcium transport. The presence of a 2-methylene group increased intestinal calcium transport activity of all four analogues above that of the native hormone, 1 alpha,25-dihydroxyvitamin D-3. In contrast, bone calcium mobilization was equal to that produced by 1 alpha,25-dihydroxyvitamin D-3 in compounds having a (20S)-configuration or diminished to one-tenth that of 1 alpha,25-dihydroxyvitamin D3 in compounds with a (20R)-configuration
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