Synthesis and Biological Activity of 1α,2α,25-Trihydroxyvitamin D₃: Active Metabolite of 2α-(3-Hydroxypropoxy)-1α,25-dihydroxyvitamin D₃ by Human CYP3A4

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).