title: 3,5-Disubstituted Isoxazole Derivatives: Potential Inhibitors of Inflammation and Cancer.
abstract: The products of arachidonic acid metabolism by lipoxygenase (LOX) and cyclooxygenase (COX) significantly contribute to inflammation and carcinogenesis. Particularly, overproduction of leukotrienes and prostaglandins contribute to tumor growth by inducing formation of new blood vessels that sustain tumor cell viability and growth. Hence, search for novel anticancer drug via inhibition of LOX and COX enzymes constitutes an impressive strategy till date. In this context, a series of isoxazole derivatives were synthesized and screened for their anti-inflammatory activity via LOX and COX inhibition. Among these, 3-(3-methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)isoxazole (2b) showed significant inhibitory activity toward LOX and COX-2. Additionally, 2b showed a good inhibition of tumor growth, peritoneal angiogenesis, and ascite formation in Ehrlich ascites carcinoma (EAC) cell mouse model. Further, the in silico molecular studies also revealed that the compound 2b binds to the catalytic domain of LOX and COX-1 and COX-2 strongly with high atomic contact energy (ACE) score compared to standard drug. These initial pharmacological data support the fact that the compound 2b serves as the basis in developing anti-inflammatory and anticancer agents.
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Crawford Hall, Mysore, 570 006, Karnataka, India.
authors.forename: Kodagahalli Sathya
authors.initials: KS
authors.lastname: Rakesh
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Crawford Hall, Mysore, 570 006, Karnataka, India.
authors.forename: Swamy
authors.initials: S
authors.lastname: Jagadish
authors.affiliation: Department of Biotechnology, Terresian College, University of Mysore, Mysore, 570 011, Karnataka, India.
authors.forename: Kyathegowdanadoddi Srinivas
authors.initials: KS
authors.lastname: Balaji
authors.affiliation: Department of Biotechnology, Biochemistry and Microbiology, Mahajana Research Foundation, SBRR Mahajana First Grade College, University of Mysore, JL Puram, Mysore, 570 012, Karnataka, India.
authors.forename: Farhan
authors.initials: F
authors.lastname: Zameer
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Crawford Hall, Mysore, 570 006, Karnataka, India.
authors.forename: Toreshettahally Ramesh
authors.initials: TR
authors.lastname: Swaroop
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Crawford Hall, Mysore, 570 006, Karnataka, India.
authors.forename: Chakrabhavi Dhanajaya
authors.initials: CD
authors.lastname: Mohan
authors.affiliation: Department of Biotechnology, Terresian College, University of Mysore, Mysore, 570 011, Karnataka, India.
authors.forename: Shankar
authors.initials: S
authors.lastname: Jayarama
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Crawford Hall, Mysore, 570 006, Karnataka, India. rangappaks@gmail.com.
authors.forename: Kanchugarakoppal Subbegowda
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D020134:Catalytic Domain / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D007555:Isoxazoles / Q000494:pharmacology*; D008084:Lipoxygenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C000612161:3-(3-methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)isoxazole; D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D016859:Lipoxygenase Inhibitors; D013876:Thiophenes; D008084:Lipoxygenase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: 3,5-disubstituted isoxazoles; carcinogenesis; cyclooxygenase; inflammation; lipoxygenase; peritoneal angiogenesis