RESUMEN
Chemotherapy is an important means of cancer treatment. However, overexpression of efflux transporters (including but not limited to P-gp and BCRP) can lead to resistance to cancer chemotherapy. Multiple-target inhibitors of efflux transporter can be overcome the resistance and improve the oral bioavailability of chemotherapy drugs. Therefore, we designed and synthesized a series of phthalazinone ring derivatives (1-20) with different aromatic heterocycles substituents on the amide bond for dual inhibition of P-gp and BCRP. Most target compounds significantly increased the accumulation of P-gp substrates in the chemo-resistant cancer cell lines by inhibiting the efflux of transporters. Compound 19 in particular showed stronger MDR reversal compared to Gefitinib and Verapamil, and comparable to that of the BCRP inhibitor Ko143. In addition, compound 19 improved intestinal absorption of paclitaxel (PTX) and enhanced the bioavailability of the orally administered drug in vivo.
Asunto(s)
Neoplasias , Paclitaxel , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Paclitaxel/farmacología , Paclitaxel/uso terapéuticoRESUMEN
Multidrug resistance (MDR) refers to the cross-resistance of cancer cells to one drug, accompanied by other drugs with different mechanisms and structures, which is one of the main obstacles of clinical chemotherapy. Overexpression of P-glycoprotein (P-gp) was an extensively studied cause of MDR. Therefore, inhibiting P-gp have become an important strategy to reverse MDR. In this study, two series of triazole-tetrahydroisoquinoline-core P-gp inhibitors were designed and synthesized. Among them, compound I-5 had a remarkable reversal activity of MDR activity and the preliminary mechanism study was also carried out. All the results proved that compound I-5 was considered as a promising P-gp-mediated MDR reversal candidate.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Diseño de Fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Tetrahidroisoquinolinas/farmacología , Triazoles/farmacología , 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 , Antibióticos Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células K562 , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Tetrahidroisoquinolinas/química , Triazoles/químicaRESUMEN
Multidrug resistance (MDR) is still the main barrier to attaining effective results with chemotherapy. Discovery of new chemo-reversal agents is needed to overcome MDR. Our study focused on a better way to obtain novel drugs with triazole rings that have an MDR reversal ability through click chemistry. Among 20 developed compounds, compound 19 had a minimal cytotoxic effect compared to tariquidar and verapamil (VRP) and showed a higher reversal activity than VRP through increased accumulation in K562/A02 cells. Compound 19 also played an important role in the P-gp efflux function of intracellular Rh123 and doxorubicin (DOX) accumulation in K562/A02 cells. Moreover, compound 19 exhibited a long lifetime of approximately 24 hr. These results indicated that compound 19 is a potential lead compound for the design of new drugs to overcome cancer MDR.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/síntesis química , Diseño de Fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antineoplásicos/farmacología , Sitios de Unión , Supervivencia Celular , Química Clic , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Células K562 , Microscopía Confocal , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Rodaminas/química , Rodaminas/metabolismo , Relación Estructura-ActividadRESUMEN
Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a phenylquinoline platform that evolved from Cinchophen lead. This design composes three sections: a phenylquinoline headgroup attached to an aliphatic carboxamides, which is tethered at a phenyl tail group. Optimization of this design led to the identification of 37, comprising a pyrrolidine linker and a trifluoromethyl-phenyl tail. In the TRPV1 functional assay, using cells expressed hTRPV1, 37 antagonized capsaicin-induced Ca2+ influx, with an IC50 value of 10.2â¯nM. In the complete mice analgesic model, 37 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that 37 could be considered as a lead candidate for the further development of antinociceptive drugs.
Asunto(s)
Analgésicos/química , Pirrolidinas/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Capsaicina/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Ratones , Dolor/tratamiento farmacológico , Dolor/patología , Dolor/veterinaria , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Solubilidad , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
Cancer chemotherapy failure is often due to the overexpression of ATP-binding cassette (ABC) transporters (particularly ABCB1), resulting in a variety of structurally and pharmacologically unrelated drugs efflux. The multidrug resistance (MDR) phenomenon could be reversed by ABCB1 inhibitors. Now, JL-A7 as the lead compound based on a triazol-N-ethyl-tetrahydroisoquinoline scaffold, 18 compounds were designed and synthesized. Substitution in para positions yielded high activities toward ABCB1. Moreover, compound 5 could effectively block the drug efflux function of ABCB1 and increase the accumulation of anti-cancer drugs to achieve effective treatment concentration in MDR cells.