TY - JOUR
T1 - 1α,20S-Dihydroxyvitamin D 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
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 1α,20S-DihydroxyVitamin D3 [1,20S(OH)2D3], a natural and bioactive Vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the Vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyVitamin D3 [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 (IFNγ and IL1β). 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)2D3 using the intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents.
AB - 1α,20S-DihydroxyVitamin D3 [1,20S(OH)2D3], a natural and bioactive Vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the Vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyVitamin D3 [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 (IFNγ and IL1β). 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)2D3 using the intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents.
UR - https://www.scopus.com/pages/publications/85028667768
U2 - 10.1038/s41598-017-10917-7
DO - 10.1038/s41598-017-10917-7
M3 - Article
C2 - 28860545
AN - SCOPUS:85028667768
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 10193
ER -