RESUMEN
The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/farmacología , Descubrimiento de Drogas , Quinazolinas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Disponibilidad Biológica , Línea Celular , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Células HEK293 , Humanos , Ratones , Simulación del Acoplamiento Molecular , Quinazolinas/administración & dosificación , Quinazolinas/química , Relación Estructura-Actividad , Fracciones Subcelulares/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new series of indole containing biaryl derivatives were designed and synthesized, and further biological evaluations of their antiproliferative activity against cancer cell lines (MGC-803 and TE-1 cells) were also conducted. Of these synthesized biaryls, compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) performed as the most potent antiproliferative agent that inhibited cell viability of MGC-803 cells with an IC50 value of 8.28 µM. In addition, investigation of mechanism exhibited that the compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) could inhibit the expression of c-Myc and glycolysis related proteins, decrease the ATP and lactate production, and further induce apoptosis by activating the AMP-activated protein kinase (AMPK) and p53 signaling pathways.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Indoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/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 , Indoles/síntesis química , Indoles/química , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
53 New drugs including 38 chemical entities and 15 biologics were approved by the U.S. Food and Drug Administration during 2020. Among the marketed drugs, 34 new small molecule drugs and 4 new diagnostic agents with privileged structures and novel clinical applications represent as promising leads for the development of new drugs with the similar indications and improved therapeutic efficacy. This review is mainly focused on the clinical applications and synthetic methods of 34 small-molecule drugs newly approved by the FDA in 2020.
