癌症中耐药性的出现是一个严重的威胁。 ABC/P-gp 转运蛋白的上调在很大程度上促成了这种现象的出现。 尽管经过 30 年的努力，对人体细胞毒性最小的有效 ABC/P-gp 抑制剂的研究仍在进行中。 受Nocardioazine A（一种抑制 P-gp 的海洋生物碱）的启发，我们报告了一种区域选择性途径来产生吲哚-C3-苄基环-L-Trp-L-Trp DKP。我们已报道，exo-C3-N-Dbn--Trp2 (13) 作为一种领先的 ABCB1 抑制剂，比维拉帕米更有效。 C3N-Dbn-Trp2 恢复了耐药人类癌细胞的化疗敏感性，并且对细胞增殖没有不利影响。 在此，我们报告了几种此类 C3 功能化吡咯并吲哚啉作为 ABCB1 抑制剂。 分子对接研究的结果表明，ABCB1 和抑制剂之间通道的相互作用是抑制剂功效的有力预测因子。基于荧光检测，我们得出结论，最有效的抑制剂是对氰基衍生的外切-C3-N-Dbn-Trp2 (33a)，紧随其后的是几种类似物。我们将基于通道处抑制剂相互作用的预测关联起来，为改进 ABCB1 抑制剂的设计提供了线索。这项工作为从环-L-Trp-L-Trp DKP 支架设计一类新型抑制剂奠定了基础。© 2024 Wiley‐VCH GmbH。

The emergence of drug resistance in cancer is a serious threat. Upregulation of ABC/P-gp transporters significantly contributes to this emergence. Despite 30 years of efforts, the search for effective ABC/P-gp inhibitors with minimal toxicity to human cells, is still underway. Inspired by Nocardioazine A, a marine alkaloid that inhibits P-gp, we report a regioselective pathway to create indole-C3-benzyl cyclo-L-Trp-L-Trp DKPs. We have reported that exo-C3-N-Dbn--Trp2 (13) as a lead ABCB1 inhibitor that is more effective than Verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells and had no adverse effect on cell proliferation. Herein, we report several such C3-functionalized pyrroloindolines as ABCB1 inhibitors. Results arising from the molecular docking studies indicate that the interactions at the access tunnel between ABCB1 and the inhibitor result in a powerful predictor for the efficacy of the inhibitor. Based on fluorescence-based assays, we conclude that the most efficacious inhibitor is the p-cyano-derived exo-C3-N-Dbn--Trp2 (33a), closely followed by several analogues. We correlate that the predictions based on the inhibitor interactions at the access tunnel provide clues about the design of improved ABCB1 inhibitors. This work lays the foundation for the design of a new class of inhibitors from a cyclo-L-Trp-L-Trp DKP scaffold.© 2024 Wiley‐VCH GmbH.