RESUMEN
c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI50 = 1.43 µM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC50 = 15 nM of c-MET) and STAT-3-IN-3 (IC50 = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.
Asunto(s)
Antineoplásicos , Proliferación Celular , Cumarinas , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Proteínas Proto-Oncogénicas c-met , Factor de Transcripción STAT3 , Tiazoles , Humanos , Cumarinas/farmacología , Cumarinas/química , Cumarinas/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Tiazoles/farmacología , Tiazoles/química , Tiazoles/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Simulación del Acoplamiento MolecularRESUMEN
Herein, we describe the design and synthesis of novel aryl pyrimidine benzenesulfonamides APBSs 5a-n, 6a-c, 7a-b, and 8 as pazopanib analogues to explore new potent and selective inhibitors for the CA IX. All APBSs were examined in vitro for their promising inhibition activity against a small panel of hCAs (isoforms I, II, IX, and XII). The X-ray crystal structure of CA I in adduct with a representative APBS analogue was solved. APBS-5m, endowed with the best hCA IX inhibitory efficacy and selectivity, was evaluated for antiproliferative activity against a small panel of different cancer cell lines, SK-MEL-173, MDA-MB-231, A549, HCT-116, and HeLa, and it demonstrated one-digit IC50 values range from 2.93 µM (MDA-MB-231) to 5.86 µM (A549). Furthermore, compound APBS-5m was evaluated for its influence on hypoxia-inducible factor (HIF-1α) production, apoptosis induction, and colony formation in MDA-MB-231 cancer cells. The in vivo efficacy of APBS-5m as an antitumor agent was additionally investigated in an animal model of Solid Ehrlich Carcinoma (SEC). In order to offer perceptions into the conveyed hCA IX inhibitory efficacy and selectivity in silico, a molecular docking investigation was also carried out.
Asunto(s)
Antineoplásicos , Inhibidores de Anhidrasa Carbónica , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Indazoles , Pirimidinas , Sulfonamidas , Humanos , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Indazoles/farmacología , Indazoles/síntesis química , Indazoles/química , Proliferación Celular/efectos de los fármacos , Animales , Relación Estructura-Actividad , Cristalografía por Rayos X , Estructura Molecular , Relación Dosis-Respuesta a Droga , Ratones , Línea Celular Tumoral , Reposicionamiento de MedicamentosRESUMEN
A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.
Asunto(s)
Antineoplásicos , Anhidrasa Carbónica IX , Inhibidores de Anhidrasa Carbónica , Cumarinas , Simulación del Acoplamiento Molecular , Tiazoles , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Cumarinas/química , Cumarinas/farmacología , Cumarinas/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Tiazoles/química , Tiazoles/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Línea Celular Tumoral , Relación Estructura-Actividad , Ratones , Cristalografía por Rayos X , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Masculino , Antígenos de Neoplasias/metabolismoRESUMEN
As a progressive neuropathic condition, glaucoma can cause lifelong blindness if left untreated. Novel phenylpyridazine-tethered sulfonamides were designed as selective inhibitors for carbonic anhydrase (CA) isoform II to find effective therapeutic agents for glaucoma. Subsequently, the target inhibitors were synthesized and assessed for their inhibitory action against cytosolic CA I and II. Interestingly, the synthesized molecules poorly inhibited CA I while exhibiting low subnanomolar potency against CA II. Compound 7c disclosed the most potent activity (IC50 = 0.63 nM) with high selectivity against CA II (605-fold than acetazolamide selectivity). Moreover, compound 7c also showed significant in vivo IOP-reducing properties in the in vivo model of glaucoma. Furthermore, the binding of compound 7c to CA II was assessed at the molecular level, exploiting the molecular docking approach.