1α,20S-Dihydroxyvitamin D Interacts with Vitamin D Receptor

Crystal Structure and Route of Chemical Synthesis

Zongtao Lin, Hao Chen, Anna Y. Belorusova, John C. Bollinger, Edith K.Y. Tang, Zorica Janjetovic, Tae Kang Kim, Zhongzhi Wu, Duane Miller, Andrzej T. Slominski, Arnold Postlethwaite, Robert C. Tuckey, Natacha Rochel, Wei Li

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number10193
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Calcitriol Receptors
Dihydroxycholecalciferols
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Calcitriol
Cholecalciferol
X Ray Crystallography
Ligands
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

1α,20S-Dihydroxyvitamin D Interacts with Vitamin D Receptor : Crystal Structure and Route of Chemical Synthesis. / Lin, Zongtao; Chen, Hao; Belorusova, Anna Y.; Bollinger, John C.; Tang, Edith K.Y.; Janjetovic, Zorica; Kim, Tae Kang; Wu, Zhongzhi; Miller, Duane; Slominski, Andrzej T.; Postlethwaite, Arnold; Tuckey, Robert C.; Rochel, Natacha; Li, Wei.

In: Scientific reports, Vol. 7, No. 1, 10193, 01.12.2017.

Research output: Contribution to journalArticle

Lin, Zongtao ; Chen, Hao ; Belorusova, Anna Y. ; Bollinger, John C. ; Tang, Edith K.Y. ; Janjetovic, Zorica ; Kim, Tae Kang ; Wu, Zhongzhi ; Miller, Duane ; Slominski, Andrzej T. ; Postlethwaite, Arnold ; Tuckey, Robert C. ; Rochel, Natacha ; Li, Wei. / 1α,20S-Dihydroxyvitamin D Interacts with Vitamin D Receptor : Crystal Structure and Route of Chemical Synthesis. In: Scientific reports. 2017 ; Vol. 7, No. 1.
@article{75c8e650f23f43f480acaa4dd1a04ce2,
title = "1α,20S-Dihydroxyvitamin D Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis",
abstract = "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.",
author = "Zongtao Lin and Hao Chen and Belorusova, {Anna Y.} and Bollinger, {John C.} and Tang, {Edith K.Y.} and Zorica Janjetovic and Kim, {Tae Kang} and Zhongzhi Wu and Duane Miller and Slominski, {Andrzej T.} and Arnold Postlethwaite and Tuckey, {Robert C.} and Natacha Rochel and Wei Li",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-10917-7",
language = "English (US)",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

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

AU - Slominski, Andrzej T.

AU - Postlethwaite, Arnold

AU - Tuckey, Robert C.

AU - Rochel, Natacha

AU - Li, Wei

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 - http://www.scopus.com/inward/record.url?scp=85028667768&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028667768&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-10917-7

DO - 10.1038/s41598-017-10917-7

M3 - Article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 10193

ER -