Low-calcemic, highly antiproliferative, 23-oxa ether analogs of the natural hormone 1 alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation.
Eight new side-chain allylic, benzylic, and propargylic ether analogs of the natural hormone calcitriol have been rationally designed and easily synthesized. Three of these 23-oxa ether analogs lacking the typical side-chain OH group are more antiproliferative in vitro and desirably less calcemic in vivo than the natural hormone. One of these three 23-oxa analogs has transcriptional potency almost as high as that of calcitriol, even though it binds to the human vitamin D receptor only about 1% as well as calcitriol.
Petersen
Kimberly S
KS
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA.
Dolan
Patrick M
PM
Kensler
Thomas W
TW
Peleg
Sara
S
Posner
Gary H
GH
D000480:Alkynes / Q000138:chemical synthesis / Q000494:pharmacology; D000498:Allyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D001667:Binding, Competitive; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002118:Calcium / Q000652:urine*; D015220:Calcium Channels / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004386:Duodenum / Q000378:metabolism; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase
D000480:Alkynes; D000498:Allyl Compounds; D001593:Benzyl Compounds; D015220:Calcium Channels; D018167:Receptors, Calcitriol; D050916:TRPV Cation Channels; C446923:Trpv6 protein, mouse; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002118:Calcium