Abstract
A practical synthetic route to novel vitamin D antagonists of DLAM (1alpha,25-dihydroxyvitamin D(3)-26,23-lactam) was developed from vitamin D(2) via the 1,3-dipolar cycloaddition reaction as a key step. Six DLAM derivatives (24 compounds) with a variety of nitrogen substituents and stereochemistries at C23 and C25 were synthesized. Among these new derivatives, (23S,25S)-DLAM isomers bound effectively to VDRs and showed antagonistic activity in the HL-60 cell differentiation inhibition assay. The importance of the substituent on the nitrogen of DLAMs for antagonistic activity was also suggested by computational docking studies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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COS Cells
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Calcitriol / analogs & derivatives*
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Calcitriol / antagonists & inhibitors*
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Calcitriol / chemical synthesis
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Calcitriol / chemistry
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Calcitriol / pharmacology
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Cell Differentiation / drug effects
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Chlorocebus aethiops
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Computational Biology
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Crystallography, X-Ray
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Drug Design
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HL-60 Cells
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Humans
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Lactams / chemical synthesis*
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Lactams / chemistry
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Lactams / pharmacology*
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Models, Molecular
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Molecular Conformation
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Protein Structure, Secondary
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Stereoisomerism
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Structure-Activity Relationship
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Vitamin D / analogs & derivatives*
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Vitamin D / antagonists & inhibitors*
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Vitamin D / chemistry
Substances
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DLAM-1P compound
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Lactams
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Vitamin D
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Calcitriol