Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alkynes / chemical synthesis
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Alkynes / pharmacology
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Allyl Compounds / chemical synthesis
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Allyl Compounds / pharmacology
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Animals
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Benzyl Compounds / chemical synthesis
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Benzyl Compounds / pharmacology
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Binding, Competitive
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Calcitriol / analogs & derivatives*
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Calcitriol / chemical synthesis*
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Calcitriol / pharmacology
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Calcium / urine*
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Calcium Channels / biosynthesis
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Calcium Channels / genetics
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Cell Line
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Cell Proliferation / drug effects*
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Duodenum / metabolism
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Female
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Humans
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Keratinocytes / cytology
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Keratinocytes / drug effects
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Mice
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Mice, Inbred C57BL
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Rats
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Receptors, Calcitriol / metabolism
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Stereoisomerism
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Steroid Hydroxylases / biosynthesis
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Steroid Hydroxylases / genetics
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Structure-Activity Relationship
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TRPV Cation Channels / biosynthesis
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TRPV Cation Channels / genetics
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Transcription, Genetic / drug effects
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Vitamin D3 24-Hydroxylase
Substances
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Alkynes
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Allyl Compounds
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Benzyl Compounds
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Calcium Channels
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Receptors, Calcitriol
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TRPV Cation Channels
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Trpv6 protein, mouse
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Steroid Hydroxylases
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Vitamin D3 24-Hydroxylase
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Calcitriol
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Calcium