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ID: ALA5137032
Journal: Eur J Med Chem
Title: Design, synthesis of DNA-interactive 4-thiazolidinone-based indolo-/pyrroloazepinone conjugates as potential cytotoxic and topoisomerase I inhibitors.
Authors: Kadagathur M, Patra S, Devabattula G, George J, Phanindranath R, Shaikh AS, Sigalapalli DK, Godugu C, Nagesh N, Tangellamudi ND, Shankaraiah N.
Abstract: With the rising cancer incidence and mortality globally, there is a prerequisite for effective design strategies towards the discovery of newer small molecular entities in chemotherapy. Hence, a series of new thiazolidinone-based indolo-/pyrroloazepinone conjugates was designed, synthesized via molecular hybridization, and evaluated for their in vitro cytotoxicity potential and DNA topoisomerase I and II inhibition. Among this series, conjugate 11g emerged as the most active compound with an IC50 value of 1.24 μM against A549 and 3.02-10.91 μM in the other tested cancer cell lines. Gratifyingly, 11g displayed 43-fold higher selectivity towards A549 cancer cells as compared to the non-cancer cells. Subsequently, conjugate 12g also demonstrated significant cytotoxicity against SK-MEL-28 cells. Basing the in vitro cytotoxicity results, SAR was established. Later, the conjugates 11g and 12g were further evaluated for their apoptosis-inducing ability, which was quantified by flow cytometric analysis, DNA-binding, Topo I inhibitory activity and IC50 value calculation. Molecular modeling studies provided profound insights about the binding nature of these compounds with DNA-Topo I complex. In silico ADME/T and prediction studies corroborated the drug-likeness of the two investigated compounds. TOPKAT toxicity profiling studies demonstrated the compounds' safety in many animal models with a minimal toxicological profile. Encouraging results obtained from in vitro and in silico studies could put this series of conjugates at the forefront of cancer drug discovery.
CiteXplore: 35635947