Investigation of 20S-hydroxyVitamin D3 analogs and their 1α-OH derivatives as potent Vitamin D receptor agonists with anti-inflammatory activities

Zongtao Lin, Srinivasa R. Marepally, Emily S.Y. Goh, Chloe Y.S. Cheng, Zorica Janjetovic, Tae Kang Kim, Duane D. Miller, Arnold E. Postlethwaite, Andrzej T. Slominski, Robert C. Tuckey, Carole Peluso-Iltis, Natacha Rochel, Wei Li

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Abstract

20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1α-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1α-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1α-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1α-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1α-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.

LanguageEnglish
Article number1478
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2018

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Calcitriol Receptors
Hydroxycholecalciferols
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Anti-Inflammatory Agents
Hydroxylation
Calcitriol
Ligands
Messenger RNA
Vitamin D3 24-Hydroxylase

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Lin, Z., Marepally, S. R., Goh, E. S. Y., Cheng, C. Y. S., Janjetovic, Z., Kim, T. K., ... Li, W. (2018). Investigation of 20S-hydroxyVitamin D3 analogs and their 1α-OH derivatives as potent Vitamin D receptor agonists with anti-inflammatory activities. Scientific Reports, 8(1), [1478]. DOI: 10.1038/s41598-018-19183-7
Lin, Zongtao ; Marepally, Srinivasa R. ; Goh, Emily S.Y. ; Cheng, Chloe Y.S. ; Janjetovic, Zorica ; Kim, Tae Kang ; Miller, Duane D. ; Postlethwaite, Arnold E. ; Slominski, Andrzej T. ; Tuckey, Robert C. ; Peluso-Iltis, Carole ; Rochel, Natacha ; Li, Wei. / Investigation of 20S-hydroxyVitamin D3 analogs and their 1α-OH derivatives as potent Vitamin D receptor agonists with anti-inflammatory activities. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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title = "Investigation of 20S-hydroxyVitamin D3 analogs and their 1α-OH derivatives as potent Vitamin D receptor agonists with anti-inflammatory activities",
abstract = "20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1α-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1α-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1α-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1α-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1α-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.",
author = "Zongtao Lin and Marepally, {Srinivasa R.} and Goh, {Emily S.Y.} and Cheng, {Chloe Y.S.} and Zorica Janjetovic and Kim, {Tae Kang} and Miller, {Duane D.} and Postlethwaite, {Arnold E.} and Slominski, {Andrzej T.} and Tuckey, {Robert C.} and Carole Peluso-Iltis and Natacha Rochel and Wei Li",
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Lin, Z, Marepally, SR, Goh, ESY, Cheng, CYS, Janjetovic, Z, Kim, TK, Miller, DD, Postlethwaite, AE, Slominski, AT, Tuckey, RC, Peluso-Iltis, C, Rochel, N & Li, W 2018, 'Investigation of 20S-hydroxyVitamin D3 analogs and their 1α-OH derivatives as potent Vitamin D receptor agonists with anti-inflammatory activities' Scientific Reports, vol. 8, no. 1, 1478. DOI: 10.1038/s41598-018-19183-7

Investigation of 20S-hydroxyVitamin D3 analogs and their 1α-OH derivatives as potent Vitamin D receptor agonists with anti-inflammatory activities. / Lin, Zongtao; Marepally, Srinivasa R.; Goh, Emily S.Y.; Cheng, Chloe Y.S.; Janjetovic, Zorica; Kim, Tae Kang; Miller, Duane D.; Postlethwaite, Arnold E.; Slominski, Andrzej T.; Tuckey, Robert C.; Peluso-Iltis, Carole; Rochel, Natacha; Li, Wei.

In: Scientific Reports, Vol. 8, No. 1, 1478, 01.12.2018.

Research output: Contribution to journalArticle

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T1 - Investigation of 20S-hydroxyVitamin D3 analogs and their 1α-OH derivatives as potent Vitamin D receptor agonists with anti-inflammatory activities

AU - Lin,Zongtao

AU - Marepally,Srinivasa R.

AU - Goh,Emily S.Y.

AU - Cheng,Chloe Y.S.

AU - Janjetovic,Zorica

AU - Kim,Tae Kang

AU - Miller,Duane D.

AU - Postlethwaite,Arnold E.

AU - Slominski,Andrzej T.

AU - Tuckey,Robert C.

AU - Peluso-Iltis,Carole

AU - Rochel,Natacha

AU - Li,Wei

PY - 2018/12/1

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