RESUMEN
A new series of 1,4-bis[5-(5-mercapto-1,3,4-oxadiazol-2-yl-methyl)-thio-4-substituted-1,2,4-triazol-3-yl]-butane 7-12 and 1,4-bis[5-(1-oxo-1-(3,5 dimethyl pyrazol-1-yl)-methyl)-thio-4-substitued-1,2,4-triazol-3-yl]-butane 13-18 were prepared from 1,4-bis(5[hydrazinocarbonylmethylthio]-4-substituted-1,2,4-triazol-3-yl) butane based derivativess were synthesized 1-6. All the synthesized compounds were characterized by IR, NMR and Mass spectral studies. The synthesized compounds 7-18 were screened for in-vitro cytotoxicity potential using the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against a panel of three human cancer cell lines: Lung carcinoma A-549, colon carcinoma HT-29 and breast cancer MDA MB-231. DNA binding studies were conducted for three potent molecules by absorption titration method.
Asunto(s)
Antineoplásicos/síntesis química , ADN/química , Sustancias Intercalantes/síntesis química , Oxadiazoles/síntesis química , Triazoles/química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromatografía en Capa Delgada , Humanos , Concentración 50 Inhibidora , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacología , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Over the past two decades, a number of chemical entities have been investigated in the continuing quest to reverse P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in cancer cells and some have undergone clinical trials, but currently none are in clinical use. Unfortunately, most of these agents suffer clinically from their intrinsic toxicity or from undesired effects on the pharmacokinetics of the accompanying anti-cancer drugs. An acridonecarboxamide (GF120918), Imidazo acridone (C(1311)) and timethylene acridone derivative 1,3-bis(9-oxoacridin-10-yl)-propane (PBA) have already been shown to be among the group of compounds known to modify P-gp mediated MDR in cancer. In the recent past it has been identified that various N(10)-substituted acridones can reverse the multidrug resistance (MDR) in cancer by selectively inhibiting the multidrug resistance associated protein (MRP) and calmodulin dependent cyclic AMP phosphodiesterase. This article envisages the various drugs being developed for treating MDR in cancer cells and especially the acridone derivatives which are being developed by the author.
Asunto(s)
Antineoplásicos/uso terapéutico , Diseño de Fármacos , Resistencia a Múltiples Medicamentos/fisiología , Neoplasias/tratamiento farmacológico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/clasificación , Transportadoras de Casetes de Unión a ATP/efectos de los fármacos , Transportadoras de Casetes de Unión a ATP/metabolismo , Acridonas/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , HumanosRESUMEN
A series of N10-substituted-2-methyl acridone derivatives are synthesized and are examined for its ability to reverse P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in breast cancer cell lines MCF-7 and MCF-7/Adr. The structural requirement of in-vitro anti-cancer and reversal of drug resistance are studied. The results showed that compound 16 with four carbon spacer exhibited promising in-vitro anti-cancer and reversal of drug resistance in comparison to the other analogues.
