Abstract
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.
Keywords: 2, 4-Disubstituted thiophene derivatives, arachidonic acid (AA), cyclooxygenase (COX-1&COX-2), EAT (Ehrlich ascites tumor) cells, heLa cell line, in vivo tumor model studies, lipoxygenase (LOX), peritoneal angiogenesis, structure-activity relationship (SAR).
Medicinal Chemistry
Title:Anti-Cancer Activity of 2,4-Disubstituted Thiophene Derivatives: Dual Inhibitors of Lipoxygenase and Cyclooxygenase
Volume: 11 Issue: 5
Author(s): Kodagahalli S. Rakesh, Swamy Jagadish, Toreshettahally R. Swaroop, Chakrabhavi D. Mohan, Nanjundaswamy Ashwini, Kachigere B. Harsha, Farhan Zameer, Kesturu S. Girish and Kanchugarakoppal S. Rangappa
Affiliation:
Keywords: 2, 4-Disubstituted thiophene derivatives, arachidonic acid (AA), cyclooxygenase (COX-1&COX-2), EAT (Ehrlich ascites tumor) cells, heLa cell line, in vivo tumor model studies, lipoxygenase (LOX), peritoneal angiogenesis, structure-activity relationship (SAR).
Abstract: 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.
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Rakesh S. Kodagahalli, Jagadish Swamy, Swaroop R. Toreshettahally, Mohan D. Chakrabhavi, Ashwini Nanjundaswamy, Harsha B. Kachigere, Zameer Farhan, Girish S. Kesturu and Rangappa S. Kanchugarakoppal, Anti-Cancer Activity of 2,4-Disubstituted Thiophene Derivatives: Dual Inhibitors of Lipoxygenase and Cyclooxygenase, Medicinal Chemistry 2015; 11 (5) . https://dx.doi.org/10.2174/1573406411666141210141918
DOI https://dx.doi.org/10.2174/1573406411666141210141918 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
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