Synthesis and biological activity of 1α,2α,25-trihydroxyvitamin D3: active metabolite of 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP3A4.
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).
Faculty of Pharmaceutical Sciences, Teikyo University.
Masashi
M
Takano
Saori
S
Ohya
Kaori
K
Yasuda
Miyu
M
Nishikawa
Akiko
A
Takeuchi
Daisuke
D
Sawada
Toshiyuki
T
Sakaki
Atsushi
A
Kittaka
D002454:Cell Differentiation / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D006887:Hydroxycholecalciferols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014815:Vitamins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
D006887:Hydroxycholecalciferols; D018167:Receptors, Calcitriol; D014815:Vitamins; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C030049:1,25,26-trihydroxyvitamin D3; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human