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Small-molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): synthesis and biological evaluation
journal contribution
posted on 2023-06-09, 12:41 authored by Salvatore Ferla, Ahmed S Aboraia, Andrea Brancale, Christopher PepperChristopher Pepper, Jinge Zhu, Justin T Ochalek, Hector F DeLuca, Claire SimonsThe 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 1a,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45a 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.
History
Publication status
- Published
File Version
- Accepted version
Journal
Journal of Medicinal ChemistryISSN
0022-2623Publisher
American Chemical SocietyExternal DOI
Issue
18Volume
57Page range
7702-7715Department affiliated with
- Clinical and Experimental Medicine Publications
Research groups affiliated with
- Haematology Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-04-04First Open Access (FOA) Date
2018-04-04First Compliant Deposit (FCD) Date
2018-04-04Usage metrics
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