Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 13, Pages 7355-7368Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00580
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- Wisconsin Alumni Research Foundation
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Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group attached to C-22 restricts the conformational flexibility of the side chain, which can result in changes in biological characteristics of a molecule. All synthesized 1 alpha,25-dihydroxy- 2,22-dimethylene-19-norvitamin D-3 analogues proved equal to calcitriol in their ability to bind to the vitamin D receptor, and most of them exert significantly higher differentiation and transcriptional activity than calcitriol. The most active compounds were characterized by the presence of an elongated side chain or 26,27-dimethylene bridge. The synthetic strategy was based on the Wittig-Horner coupling of the known A-ring phosphine oxide with the corresponding Grundmann ketones prepared from a 20-epi-Inhoffen-Lythgoe diol derived from vitamin D-2.
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