Small-molecule inhibitors of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1): synthesis and biological evaluation

Ferla, Salvatore ORCID: https://orcid.org/0000-0002-5918-9237, Aboraia, Ahmed S., Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Pepper, Christopher J., Zhu, Jinge, Ochalek, Justin T., DeLuca, Hector F. and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2014. Small-molecule inhibitors of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1): synthesis and biological evaluation. Journal of Medicinal Chemistry 57 (18) , pp. 7702-7715. 10.1021/jm5009314

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Abstract

The synthesis of imidazole styrylbenzamide, tert-butyl styrylimidazole, and tert-butyl styrylsulfonate derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivity with respect to CYP27B1 comparable with or greater than that of the standard ketoconazole. Further evaluation of the 3,5-dimethoxy and 3,4,5-trimethoxy derivatives in chronic lymphocytic leukemia cells revealed that co-treatment of 1α,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45α and CDKN1A. Docking experiments on the inhibitors in the CYP24A1 enzyme active site suggest the compounds reach the active site through the vitamin D access tunnel and are exposed to multiple hydrophobic residues. The imidazole styrylbenzamides are optimally positioned to allow interaction of the imidazole with the heme, and, in the case of the methoxy derivatives, a hydrogen bond between the 3-methoxy group and Gln82 stabilizes the molecule in a favorable active conformation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Medicine
Subjects:	Q Science > QD Chemistry R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	30 March 2016
Last Modified:	10 Nov 2024 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/69384

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