RESUMEN
Based on our previous results and literature precedence, a series of 2-anilinopyridinyl-benzothiazole Schiff bases were rationally designed by performing molecular modeling experiments on some selected molecules. The binding energies of the docked molecules were better than the E7010, and the Schiff base with trimethoxy group on benzothiazole moiety, 4y was the best. This was followed by the synthesis of a series of the designed molecules by a convenient synthetic route and evaluation of their anticancer potential. Most of the compounds have shown significant growth inhibition against the tested cell lines and the compound 4y exhibited good antiproliferative activity with a GI50 value of 3.8µM specifically against the cell line DU145. In agreement with the docking results, 4y exerted cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, comparable to E7010. Detailed binding modes of 4y with colchicine binding site of tubulin were studied by molecular docking. Furthermore, 4y induced apoptosis as evidenced by biological studies like mitochondrial membrane potential, caspase-3, and Annexin V-FITC assays.
Asunto(s)
Antimitóticos/síntesis química , Benzotiazoles/química , Diseño de Fármacos , Bases de Schiff/síntesis química , Moduladores de Tubulina/síntesis química , Antimitóticos/química , Antimitóticos/toxicidad , Benzotiazoles/síntesis química , Benzotiazoles/toxicidad , Sitios de Unión , Unión Competitiva , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Bases de Schiff/química , Bases de Schiff/toxicidad , Relación Estructura-Actividad , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidadRESUMEN
A new class of combretastatin linked 1,3,4-oxadiazoles were designed, synthesized and screened for their cytotoxic activity against five human cancer cell lines such as HeLa, DU-145, A549, MDA-MB-231 and B16. These compounds showed significant cytotoxicity with IC50 values in the range 0.118-54.32µM. Conjugate 5m displayed potent antiproliferative activity against DU-145 cell line. Flow cytometric analysis revealed that these compounds arrested the cell cycle in G2/M phase. Moreover, the tubulin polymerization assay and immunofluorescence analysis indicate that 5m exhibits potent inhibitory effect on the tubulin assembly. Further, DNA fragmentation and Hoecst staining assays confirm that 5m induces apoptosis. Molecular docking studies and competitive binding assay indicated that 5m effectively bind at the colchicine binding site of the tubulin.
Asunto(s)
Antineoplásicos/farmacología , Bibencilos/farmacología , Oxadiazoles/farmacología , Polimerizacion/efectos de los fármacos , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bibencilos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Inmunohistoquímica , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxadiazoles/química , Relación Estructura-Actividad , Tubulina (Proteína)/análisis , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/químicaRESUMEN
A series of anilinonicotinyl linked pyrazolo[1,5-a]pyrimidine conjugates (6a-x) were synthesized and evaluated for their antiproliferative activity. Some of these conjugates exhibited promising cytotoxic effects in the MCF-7 cell line and among these 6a and 6c exhibited significant effects, apart from G2/M cell cycle arrest. Interestingly they showed profound effects on cyclin D1, Bcl-2 and survivin proteins that regulate breast cancer cell proliferation. Moreover, ER alpha protein expression was studied to understand regulatory role of these conjugates on estrogen activity in estrogen positive breast cancer cells like MCF-7 and compounds 6a and 6c reduced their activity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Estrógenos/metabolismo , Nicotina/análogos & derivados , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Estructura Molecular , Nicotina/síntesis química , Nicotina/química , Nicotina/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
A series of 5-nitrofuran-triazole congeners were designed and synthesized by carrying out suitable structural modifications of the previously reported counterparts and were evaluated for their antimicrobial potential against both Gram-positive and Gram-negative bacterial strains. The compounds exhibited promising inhibition towards different Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 9f, 9g, 9l and 9m were most active among the series, exhibiting a MIC value of 1.9 µg mL(-1) against different bacterial strains. The bactericidal activity was found to be in coherence with the bacterial growth inhibition data. The compounds were tested against fourteen different fungal strains and were found to possess excellent antifungal activities. Interestingly, all the compounds were equipotent to miconazole against one or more of the tested fungal strains and showed good activity against the other counterparts. A similar trend was observed in the case of their minimum fungicidal concentration values. Moreover, compound 9f exhibited two fold superior antifungal activity (MIC = 3.9 µg mL(-1)) than the standard miconazole (MIC = 7.8 µg mL(-1)) against C. albicans and C. parapsilosis. These compounds also effectively inhibited biofilm formation and compound 9f exhibited excellent anti-biofilm activity demonstrating a biofilm inhibitory concentration (BIC) as low as 0.8 µg mL(-1). A brief mechanistic study carried out on the most effective conjugate 9f indicated that it inhibits the ergosterol biosynthesis, thereby exhibiting antifungal effects. Molecular modelling studies carried out to study the binding modes of 9f correlates well with the antifungal activity and supported by ergosterol biosynthesis inhibition assay data. Most of these compounds exhibited ten times lower cytotoxicity toward the normal cells compared to the antimicrobial activity.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/farmacología , Nitrofuranos/farmacología , Triazoles/farmacología , Antibacterianos/química , Antifúngicos/química , Candida/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Ergosterol/antagonistas & inhibidores , Ergosterol/biosíntesis , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Nitrofuranos/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
A simple, mild and efficient method for the synthesis of pyrazolopyridine based spirooxindoles by the three-component reaction has been developed using sulfamic acid (H2NSO3H) as a green catalyst. The method involves use of water as a solvent which makes it eco-friendly. The catalyst used is readily available and is prominent for short reaction time, operational simplicity and high yields. After completion of the reaction the catalyst could be recovered and reused for up to four cycles without loss in catalytic activity. Employing this method a library of 34 compounds has been synthesized and investigated for their cytotoxicity against a panel of three human cancer cell lines. Some of the compounds like 4o and 4p exhibited remarkable cytotoxicities with IC50 values of 0.35µM and 1.92µM against MDA-MB-231 cell line.
Asunto(s)
Indoles/síntesis química , Indoles/toxicidad , Ácidos Sulfónicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Catálisis , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Indoles/química , Indoles/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Oxindoles , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/toxicidadRESUMEN
A series of 2-anilinopyridine dimers have been synthesized and evaluated for their anticancer potential. Most of the compounds have showed significant growth inhibition of the cell lines tested and compound 4d was most effective amongst the series displaying a GI50 of 0.99 µM specifically against the prostate cancer cell line (DU145). Studies to understand the mechanism of action of 4d indicates that it disrupts microtubule dynamics by inhibiting tubulin polymerization thereby arresting the cell cycle in G2/M phase. Competitive colchicine binding assay suggests that 4d binds into colchicine binding site of the tubulin. Further from some detailed biological studies like mitochondrial membrane potential, caspase-3 assay, DNA fragmentation analysis and Annexin V-FITC assay it is evident that 4d induces apoptosis.Molecular modeling studies provide an insight into the binding modes of 4d with colchicine binding site of tubulin and the data obtained correlates with the antiproliferative activity.