1 alpha,20S-Dihydroxyvitamin D-3 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 D. Miller, Andrzej T. Slominski, Arnold E. Postlethwaite, Robert C. Tuckey, Natacha Rochel, Wei Li

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article number10193
Number of pages10
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 31 Aug 2017

Cite this

Lin, Zongtao ; Chen, Hao ; Belorusova, Anna Y. ; Bollinger, John C. ; Tang, Edith K. Y. ; Janjetovic, Zorica ; Kim, Tae-Kang ; Wu, Zhongzhi ; Miller, Duane D. ; Slominski, Andrzej T. ; Postlethwaite, Arnold E. ; Tuckey, Robert C. ; Rochel, Natacha ; Li, Wei. / 1 alpha,20S-Dihydroxyvitamin D-3 Interacts with Vitamin D Receptor : Crystal Structure and Route of Chemical Synthesis. In: Scientific Reports. 2017 ; Vol. 7.
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title = "1 alpha,20S-Dihydroxyvitamin D-3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis",
abstract = "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.",
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author = "Zongtao Lin and Hao Chen and Belorusova, {Anna Y.} and Bollinger, {John C.} and Tang, {Edith K. Y.} and Zorica Janjetovic and Tae-Kang Kim and Zhongzhi Wu and Miller, {Duane D.} and Slominski, {Andrzej T.} and Postlethwaite, {Arnold E.} and Tuckey, {Robert C.} and Natacha Rochel and Wei Li",
year = "2017",
month = "8",
day = "31",
doi = "10.1038/s41598-017-10917-7",
language = "English",
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journal = "Scientific Reports",
issn = "2045-2322",
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Lin, Z, Chen, H, Belorusova, AY, Bollinger, JC, Tang, EKY, Janjetovic, Z, Kim, T-K, Wu, Z, Miller, DD, Slominski, AT, Postlethwaite, AE, Tuckey, RC, Rochel, N & Li, W 2017, '1 alpha,20S-Dihydroxyvitamin D-3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis' Scientific Reports, vol. 7, 10193. https://doi.org/10.1038/s41598-017-10917-7

1 alpha,20S-Dihydroxyvitamin D-3 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 D.; Slominski, Andrzej T.; Postlethwaite, Arnold E.; Tuckey, Robert C.; Rochel, Natacha; Li, Wei.

In: Scientific Reports, Vol. 7, 10193, 31.08.2017.

Research output: Contribution to journalArticle

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

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 10193

ER -