Abstract
Our previous studies revealed that recombinant human CYP3A4 converted 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 (O2C3), which was a more potent binder to vitamin D receptor (VDR) than the natural hormone, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3, 1), to 1α,2α,25-trihydroxyvitamin D3 (2). Here, we synthesized 2 using the Trost Pd-mediated coupling reaction between an A-ring precursor and a CD-ring bromoolefin and evaluated its preliminary biological activity. We found that metabolite 2 from O2C3 was still active as a VDR ligand while maintaining human VDR binding affinity (27.3% of 1α,25(OH)2D3) and HL-60 cell differentiation activity (62% of 1α,25(OH)2D3).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / drug effects
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Cytochrome P-450 CYP3A / metabolism*
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HL-60 Cells
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Humans
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Hydroxycholecalciferols / chemistry
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Hydroxycholecalciferols / metabolism*
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Hydroxycholecalciferols / pharmacology*
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Protein Binding
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Receptors, Calcitriol / metabolism
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Vitamin D / analogs & derivatives*
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Vitamin D / chemistry
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Vitamin D / metabolism
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Vitamin D / pharmacology
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Vitamins / chemistry
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Vitamins / metabolism*
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Vitamins / pharmacology*
Substances
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Hydroxycholecalciferols
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Receptors, Calcitriol
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Vitamins
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dihydroxy-vitamin D3
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Vitamin D
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1,25,26-trihydroxyvitamin D3
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human