RESUMEN
A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies.
Asunto(s)
Antineoplásicos/farmacología , Quinolinas/farmacología , Tiofenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Caspasa 9/metabolismo , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Receptores ErbB/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Células MCF-7 , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
A series of new coumarin containing compounds were synthesized from 4-bromomethylcoumarin derivatives 2a, b and different heteroaromatic systems 4a-e, 6a-d, 8, 10via methylene thiolinker. Twenty-four compounds were screened biologically against two human tumor cell lines, breast carcinoma MCF-7 and hepatocellular carcinoma HePG-2, at the national cancer institute, Cairo, Egypt using 5-fluorouracil as standard drug. Compounds 5h, 7d, 7h, 9a, 13a and 13d showed strong activity against both MCF-7 and HepG-2 cell lines with being compound 13a is the most active with IC50 values of 5.5 µg/ml and 6.9 µg/ml respectively. Docking was performed with protein 1KE9 to study the binding mode of the designed compounds.