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Novel azolyl-(phenylmethyl)]aryl/heteroarylamines: Potent CYP26 inhibitors and enhancers of all-trans retinoic acid activity in neuroblastoma cells

Gomaa, Mohamed Sayed, Armstrong, Jane L., Bobillon, Beatrice, Veal, Gareth J., Brancale, Andrea, Redfern, Christopher P.F. and Simons, Claire 2008. Novel azolyl-(phenylmethyl)]aryl/heteroarylamines: Potent CYP26 inhibitors and enhancers of all-trans retinoic acid activity in neuroblastoma cells. Bioorganic & Medicinal Chemistry 16 (17) , pp. 8301-8313. 10.1016/j.bmc.2007.06.048

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Abstract

The synthesis and potent inhibitory activity of novel 4-[(imidazol-1-yl and triazol-1-yl)(phenyl)methyl]aryl-and heteroaryl amines versus a MCF-7 CYP26A1 cell assay is described. Biaryl imidazole ([4-(imidazol-1-yl-phenyl-methyl)-phenyl]-naphthalen-2- yl-amine (8), IC50 = 0.5 lM; [4-(imidazol-1-yl-phenyl-methyl)-phenyl]-indan-5-yl-amine (9), IC50 = 1.0 lM) and heteroaryl imidazole derivatives ((1H-benzoimidazol-2-yl)-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (15), IC50 = 2.5 lM; benzooxazol-2-yl- {4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (16), IC50 = 0.9 lM; benzothiazol-2-yl-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}- amine (17), IC50 = 1.5 lM) were the most potent CYP26 inhibitors. Using a CYP26A1 homology model differences in activity were investigated. Incubation of SH-SY5Y human neuroblastoma cells with the imidazole aryl derivative 8, and the imidazole heteroaryl derivatives 16 and 17 potentiated the atRA-induced expression of CYP26B1. These data suggest that further structure– function studies leading to clinical development are warranted.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: 4-[(Imidazol-1-yl and triazol-1-yl)(phenyl)methyl]aryl- and heteroaryl amines ; IC50 enzyme inhibition ; Retinoic acid metabolism blocking agents (RAMBAs); MCF-7 ; CYP26A1 ; Molecular modelling ; Neuroblastoma.
Publisher: Elsevier
ISSN: 0968-0896
Last Modified: 02 Jun 2019 22:51
URI: http://orca-mwe.cf.ac.uk/id/eprint/7474

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