title: Small-molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): synthesis and biological evaluation.
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.
authors.affiliation: Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ferla
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Aboraia
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pepper
authors.forename: Jinge
authors.initials: J
authors.lastname: Zhu
authors.forename: Justin T
authors.initials: JT
authors.lastname: Ochalek
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology; D008958:Models, Molecular; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D065668:Vitamin D3 24-Hydroxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D006418:Heme; D065668:Vitamin D3 24-Hydroxylase