Small-Molecule Inhibitors of 25-Hydroxyvitamin D‑24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation

• Published in: Journal of medicinal chemistry Vol. 57; no. 18; pp. 7702 - 7715
• Main Authors: Ferla, Salvatore, Aboraia, Ahmed S, Brancale, Andrea, Pepper, Christopher J, Zhu, Jinge, Ochalek, Justin T, DeLuca, Hector F, Simons, Claire
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.09.2014; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Catalytic Domain; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Cytochrome P-450 Enzyme Inhibitors - chemical synthesis; Cytochrome P-450 Enzyme Inhibitors - chemistry; Cytochrome P-450 Enzyme Inhibitors - metabolism; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Heme - metabolism; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - metabolism; Imidazoles - pharmacology; Inhibitory Concentration 50; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Life Sciences & Biomedicine; Models, Molecular; Pharmacology & Pharmacy; Science & Technology; Sequence Homology, Amino Acid; Structure-Activity Relationship; Vitamin D3 24-Hydroxylase - antagonists & inhibitors; Vitamin D3 24-Hydroxylase - chemistry; VITAMIN-D; MULTIPLE-SCLEROSIS; METABOLISM; ANALOGS; BINDING-AFFINITY; COMPLEXES; GROWTH; SELECTIVE INHIBITORS; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; PREDICTION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5009314

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.