Polymethoxylated N ‐Carboranyl Isoquinolinones: A New Scaffold for ABCG2 Inhibitors

ABCG2‐mediated multidrug resistance (MDR) is a major challenge among chemotherapeutic treatments of colon, pancreatic, and breast cancer, as well as leukemia. Clinical oncology seeks new adjuvant therapeutics to overcome MDR by developing potent but nontoxic ABCG2 inhibitors. Aided by computational docking analyses, based on known substrate and inhibitor structural motifs, a new isoquinolinone framework and several (poly)methoxylated derivatives were designed and synthesized. The novel carborane‐containing N ‐carboranyl isoquinolinones were evaluated for cytotoxicity, ABCG2 inhibition, and reversal of MDR in combination with mitoxantrone (MXN) in an ABCG2‐expressing Madin–Darby canine kidney II cell model. While the parental compound IC‐1 showed strong ABCG2 inhibition, its 4‐methoxyphenyl, 3,4‐dimethoxyphenyl, and 3,4,5‐trimethoxyphenyl derivatives ( IC‐4 , IC‐5, and IC‐6 ) exhibited improved ABCG2 affinity. Nonsubstituted isoquinolinones IC‐1 to IC‐6 displayed higher solubility, lower toxicity, and similar ABCG2 inhibition and reversal of MXN resistance than 6,7‐dimethoxy‐isoquinolinone derivatives IC‐7 to IC‐11 . Especially, the 4‐methoxyphenyl‐ and 3,4‐dimethoxyphenyl‐substituted isoquinolinones ( IC‐10 , IC‐11 ) caused the strongest left shift of the MXN IC 50 value by 8.1‐ and 7.2‐fold, indicating effective resensitization to the chemotherapeutic agent. Therefore, carborane‐containing isoquinolinones featuring additional methoxy groups represent a promising approach for the development of ABCG2 inhibitors to overcome resistance to anticancer drugs.