Synthesis and biological activity of 1a,2a,25-Trihydroxyvitamin D3: Active metabolite of 2a-(3-Hydroxypropoxy)-1a,25-dihydroxyvitamin D3 by human CYP3A4

Abstract

Our previous studies revealed that recombinant human CYP3A4 converted 2a-(3-hydroxypropoxy)-1a,25- dihydroxyvitamin D3 (O2C3), which was a more potent binder to vitamin D receptor (VDR) than the natural hormone, 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3, 1), to 1a,2a,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 1a,25(OH)2D3) and HL-60 cell differentiation activity (62% of 1a,25(OH)2D3). © 2014 The Pharmaceutical Society of Japan.