Abstract
New C,D-ring side-chain-modified sulfone 4a, with natural 1alpha, 3beta-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1), has been prepared and characterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermediate and (2) smooth reductive etherification without interference by a neighboring sulfonyl group. Sulfone 4a, but not its 1beta, 3alpha-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resemble Leo Pharmaceutical Co.'s KH-1060 (3), is recognized by catabolic enzymes, the selective biological profile of sulfone 4a is likely not due to its metabolites that are formed in only minor amounts.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / 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 / chemistry
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Calcitriol / pharmacology
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Cell Division / drug effects
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Graft Rejection
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Humans
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Immunosuppressive Agents / chemical synthesis
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology
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Islets of Langerhans Transplantation
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Mice
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Mice, Inbred BALB C
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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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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
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Transcription, Genetic / drug effects
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Immunosuppressive Agents
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Receptors, Calcitriol
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Sulfones
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Calcitriol