TY - JOUR
T1 - Synthesis and biological activity of 1a,2a,25-Trihydroxyvitamin D3
T2 - Active metabolite of 2a-(3-Hydroxypropoxy)-1a,25-dihydroxyvitamin D3 by human CYP3A4
AU - Takano, Masashi
AU - Ohya, Saori
AU - Yasuda, Kaori
AU - Nishikawa, Miyu
AU - Takeuchi, Akiko
AU - Sawada, Daisuke
AU - Sakaki, Toshiyuki
AU - Kittaka, Atsushi
PY - 2014/2
Y1 - 2014/2
N2 - 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).
AB - 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).
KW - 1a,2a,25-trihydroxyvitamin D3
KW - CYP24A1
KW - CYP3A4
KW - Cell differentiation
KW - Vitamin D receptor
UR - http://www.scopus.com/inward/record.url?scp=84894257156&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84894257156&partnerID=8YFLogxK
U2 - 10.1248/cpb.c13-00646
DO - 10.1248/cpb.c13-00646
M3 - Article
C2 - 24492588
AN - SCOPUS:84894257156
SN - 0009-2363
VL - 62
SP - 182
EP - 184
JO - Chemical and Pharmaceutical Bulletin
JF - Chemical and Pharmaceutical Bulletin
IS - 2
ER -