Anti-Cancer Activity of 2,4-Disubstituted Thiophene Derivatives: Dual Inhibitors of Lipoxygenase and Cyclooxygenase

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 11; no. 5; p. 462
• Main Authors: Rakesh, Kodagahalli S, Jagadish, Swamy, Swaroop, Toreshettahally R, Mohan, Chakrabhavi D, Ashwini, Nanjundaswamy, Harsha, Kachigere B, Zameer, Farhan, Girish, Kesturu S, Rangappa, Kanchugarakoppal S
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2015
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Survival - drug effects; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; HeLa Cells; Humans; Inhibitory Concentration 50; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Mice; Models, Molecular; Molecular Docking Simulation; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 1875-6638
• DOI: 10.2174/1573406411666141210141918

2,4-Disubstituted thiophene derivatives were synthesized and assessed for antiinflammatory and anti-cancer activities by targeting two important enzymes of the arachidonic acid metabolism. Both lipoxygenase and cyclooxygenase enzymes play vital role in chronic inflammation and carcinogenesis. Previous studies have proved that COX-2 and 5-LOX are highly activated in various types of cancers; hence inhibition of these clinically important enzymes constitutes the essential criterion for the suppression of tumor progression and metastasis. Among the tested derivatives, 2d and 2g compounds emerged as potent inhibitors of lipoxygenase and cyclooxygenase enzymes. The potent inhibitor of cyclooxygenase was further tested for in vitro cytotoxicity on cervical cancer (HeLa) cells and in vivo tumor model studies using EAT bearing mice where 2-(3,4,5- trimethoxyphenyl)-4-(N-methylindol-3-yl) thiophene (2g) showed eloquent activity. Further, in silico modeling results confirmed the active catalytic ligand binding pockets, which is evident from higher atomic contact energy values of 2d and 2g than compared to standard drug. Thus, 2g may find better application in management of inflammation and in proapoptotic therapeutic engineering.