TY - JOUR
T1 - 1 alpha,20S-Dihydroxyvitamin D-3 Interacts with Vitamin D Receptor
T2 - Crystal Structure and Route of Chemical Synthesis
AU - Lin, Zongtao
AU - Chen, Hao
AU - Belorusova, Anna Y.
AU - Bollinger, John C.
AU - Tang, Edith K. Y.
AU - Janjetovic, Zorica
AU - Kim, Tae-Kang
AU - Wu, Zhongzhi
AU - Miller, Duane D.
AU - Slominski, Andrzej T.
AU - Postlethwaite, Arnold E.
AU - Tuckey, Robert C.
AU - Rochel, Natacha
AU - Li, Wei
PY - 2017/8/31
Y1 - 2017/8/31
N2 - 1 alpha, 20S-Dihydroxyvitamin D3 [1,20S(OH)(2)D-3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1 alpha-OH configuration. 1,20S(OH)(2)D-3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1 alpha, 25-dihydroxyvitamin D-3 [1,25(OH) 2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFN gamma and IL1 beta). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)(2)D-3 using the intermediate 1 alpha, 3 beta-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)(2)D-3 and its analogs as potential therapeutic agents.
AB - 1 alpha, 20S-Dihydroxyvitamin D3 [1,20S(OH)(2)D-3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1 alpha-OH configuration. 1,20S(OH)(2)D-3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1 alpha, 25-dihydroxyvitamin D-3 [1,25(OH) 2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFN gamma and IL1 beta). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)(2)D-3 using the intermediate 1 alpha, 3 beta-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)(2)D-3 and its analogs as potential therapeutic agents.
KW - 20S-HYDROXYVITAMIN D3
KW - BIOLOGICAL-ACTIVITIES
KW - CYTOCHROME P450SCC
KW - MELANOMA-CELLS
KW - ANALOGS
KW - METABOLISM
U2 - 10.1038/s41598-017-10917-7
DO - 10.1038/s41598-017-10917-7
M3 - Article
C2 - 28860545
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 10193
ER -