Investigation of 20S-hydroxyvitamin D3 analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-01-24

AUTHORS

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

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. More... »

PAGES

1478

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-19183-7

DOI

http://dx.doi.org/10.1038/s41598-018-19183-7

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1100512224

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29367669


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72 potential
73 receptor agonist
74 receptors
75 scaffolds
76 side chain composition
77 side chains
78 stability
79 stimulating activity
80 strong activity
81 study
82 substrate
83 subtle differences
84 synthesis
85 vitamin D receptor agonists
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