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: Kodagahalli Sathya Rakesh, Swamy Jagadish, Kyathegowdanadoddi Srinivas Balaji, Farhan Zameer, Toreshettahally Ramesh Swaroop, Chakrabhavi Dhanajaya Mohan, Shankar Jayarama, Kanchugarakoppal Subbegowda Rangappa
• Journal: Inflammation (Inflammation) Vol. 39 Issue 1 Pg. 269-280 (Feb 2016) ISSN: 1573-2576 [Electronic] United States
• PMID: 26363638 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(3-methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)isoxazole
• Angiogenesis Inhibitors
• Anti-Inflammatory Agents
• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Isoxazoles
• Lipoxygenase Inhibitors
• Thiophenes
• Lipoxygenase
• Ptgs2 protein, mouse
• Cyclooxygenase 2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antineoplastic Agents (pharmacology)
• Binding Sites (drug effects)
• Carcinoma, Ehrlich Tumor (drug therapy)
• Catalytic Domain (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Disease Models, Animal
• HeLa Cells
• Humans
• Inflammation (drug therapy)
• Isoxazoles (pharmacology)
• Lipoxygenase (metabolism)
• Lipoxygenase Inhibitors (pharmacology)
• Mice
• Molecular Docking Simulation
• Thiophenes (pharmacology)