Abstract：
: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 1α,25-dihydroxy-2,22-dimethylene-19-norvitamin D3 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 D2.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Sibilska-Kaminski IK,Sicinski RR,Plum LA,DeLuca HFdoi
10.1021/acs.jmedchem.0c00580subject
Has Abstractpub_date
2020-07-09 00:00:00pages
7355-7368issue
13eissn
0022-2623issn
1520-4804journal_volume
63pub_type
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