Novel azolyl-(phenylmethyl)]aryl/heteroarylamines: potent CYP26 inhibitors and enhancers of all-trans retinoic acid activity in neuroblastoma cells.
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), IC(50)=0.5 microM; [4-(imidazol-1-yl-phenyl-methyl)-phenyl]-indan-5-yl-amine (9), IC(50)=1.0 microM) and heteroaryl imidazole derivatives ((1H-benzoimidazol-2-yl)-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (15), IC(50)=2.5 microM; benzooxazol-2-yl-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (16), IC(50)=0.9 microM; benzothiazol-2-yl-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (17), IC(50)=1.5 microM) 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.
Gomaa
Mohamed Sayed
MS
Medicinal Chemistry Division, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
Armstrong
Jane L
JL
Bobillon
Beatrice
B
Veal
Gareth J
GJ
Brancale
Andrea
A
Redfern
Christopher P F
CP
Simons
Claire
C
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D000072516:Retinoic Acid 4-Hydroxylase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012984:Software; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000494:pharmacology*
D000588:Amines; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D012333:RNA, Messenger; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; D000072516:Retinoic Acid 4-Hydroxylase