Flavonoid dimers and methods of making and using such

Abstract

Multidrug resistance (MDR) is a major problem in cancer chemotherapy. The best characterized resistance mechanism is the one mediated by the over- expression of drug efflux transporters, permeability-glycoprotein (P-gp), which pump a variety of anticancer drugs out of the cells, resulting in lowered intracellular drug accumulation. A series of flavonoid dimers are developed in this invention, which are linked together by linker groups of various lengths. These flavonoid dimers are found to be efficient P-gp modulators that increase cytotoxicity of anticancer drugs in vitro and dramatically enhance their intracellular drug accumulation. It is found that the flavonoid dimers of this invention are also useful in reducing drug resistance in treating parasitic diseases. 多药耐药性(MDR)是癌症化学治疗中的主要问题。最好的特征性耐药机制是由将各种抗癌药物泵出细胞、导致细胞内药物累积量降低的药物流出转运体——渗透性糖蛋白(P-gp)的过度表达所介导的机制。本发明开发了一系列通过各种长度的连接基团连接在一起的类黄酮二聚物。发现这些类黄酮二聚物是增加抗癌药物的体外细胞毒性并大大增强它们的细胞内药物累积的有效的P-gp调节剂。发现本发明的类黄酮二聚物也可用于在治疗寄生性疾病时降低药物耐受性。