RESUMEN
Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20â¯cells, and sensitized NCI-H460/MX20â¯cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Antineoplásicos/farmacología , Dicetopiperazinas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Dicetopiperazinas/química , Dicetopiperazinas/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/metabolismo , Humanos , Estructura Molecular , Proteínas de Neoplasias/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A versatile Lewis acid catalyzed tandem cyclization of in situ generated alkynyl o-quinone methides ( o-AQMs) with electron-rich phenols has been developed on the basis of the mode involving an intermolecular 1,4-conjugate addition/6-endo cyclization/1,3-aryl shift/intramolecular 1,4-conjugate addition cascade. This reaction provides a new method for expeditious assembly of synthetically and biologically interesting tetracyclic bridged dioxabicyclo[3.3.1]nonane skeletons featuring a congested bridgehead oxa-quaternary stereocenter.
