化疗的成功往往受到多药耐药的阻碍。其中一种耐药机制是通过药物转运蛋白，如乳腺癌耐药蛋白（BCRP；又称ABCG2）的抗癌药物排出，导致人类患者的5年存活率较低。联合化疗药物和天然化合物（如黄芩素）的治疗可预防药物耐药，但受到快速代谢的限制。基于硼簇（如间甲基二十面体硼）的苯类模拟物对增加靶点亲和力非常有前景；因此，我们研究了用间甲基二十面体硼替代黄芩素中的苯环，以提高其对人类ABCG2外排转运蛋白的亲和力。黄芩素强烈抑制了ABCG2介导的外排，导致丝裂霉素的细胞毒性增加五倍。而黄芩素衍生物5,6,7-三甲氧基黄酮在5 μM的浓度下抑制了ABCG2的外排活性，但无法逆转丝裂霉素的耐药性，而其间甲基二十面体硼类似物5,6,7-三甲氧基硼黄酮在纳摩尔范围（0.1 μM）内显著增强了抑制效果，并且引起了丝裂霉素毒性的增加，达到了强效的ABCG2抑制剂Ko143的效果。总体而言，体外分析和体内对接实验表明，将黄芩素修饰为间甲基二十面体硼和三个甲氧基取代基可增强ABCG2介导的耐药性逆转。因此，这似乎是开发高效ABCG2抑制剂的有希望基础。本文章受版权保护。保留所有权利。

Success of chemotherapy is often hampered by multidrug resistance. One mechanism for drug resistance is the elimination of anticancer drugs through drug transporters, such as breast cancer resistance protein (BCRP; also known as ABCG2), and causes a poor 5-year survival rate of human patients. Co-treatment of chemotherapeutics and natural compounds, such as baicalein, is used to prevent chemotherapeutic resistance but is limited by rapid metabolism. Boron-based clusters as meta-carborane are very promising phenyl mimetics to increase target affinity; we therefore investigated the replacement of a phenyl ring in baicalein by a meta-carborane to improve its affinity towards the human ABCG2 efflux transporter. Baicalein strongly inhibited the ABCG2-mediated efflux and caused a five-fold increase of mitoxantrone cytotoxicity. Whereas the baicalein derivative 5,6,7-trimethoxyflavone inhibited ABCG2 efflux activity in a concentration of 5 μM without reversing mitoxantrone resistance, its carborane analogue 5,6,7-trimethoxyborcalein significantly enhanced the inhibitory effects in nanomolar ranges (0.1 μM) and caused a stronger increase of mitoxantrone toxicity reaching similar values as Ko143, a potent ABCG2 inhibitor. Overall, in silico docking and in vitro studies demonstrated that the modification of baicalein with meta-carborane and three methoxy substituents leads to an enhanced reversal of ABCG2-mediated drug resistance. Thus, this seems to be a promising basis for the development of efficient ABCG2 inhibitors.This article is protected by copyright. All rights reserved.