EA 4446 Bioactive Molecules and Medicinal Chemistry, Université Claude Bernard Lyon 1, 69373, Lyon, France; Drug Resistance & Membrane Proteins Group - Molecular Microbiology and Structural Biochemistry Laboratory, CNRS-UCBL1 UMR 5086, IBCP, 69367, Lyon, France.
EA 4446 Bioactive Molecules and Medicinal Chemistry, Université Claude Bernard Lyon 1, 69373, Lyon, France; Laboratory of Applied Organic Chemistry, Synthesis of Biomolecules and Molecular Modelling Group, Badji Mokhtar - Annaba University, 23000, Annaba, Algeria.
Eur J Med Chem. 2021 Feb 5;211:113017. doi: 10.1016/j.ejmech.2020.113017. Epub 2020 Nov 12.
Multidrug resistance membrane pumps reduce the efficacy of chemotherapies by exporting a wide panel of structurally-divergent drugs. Here, to take advantage of the polyspecificity of the human Breast Cancer Resistance Protein (BCRP/ABCG2) and the dimeric nature of this pump, new dimeric indenoindole-based inhibitors from the monomeric α,β-unsaturated ketone 4b and phenolic derivative 5a were designed. A library of 18 homo/hetero-dimers was synthesised. Homo-dimerization shifted the inhibition efficacy from sub-micromolar to nanomolar range, correlated with the presence of 5a, linked by a 2-6 methylene-long linker. Non-toxic, the best dimers displayed a therapeutic ratio as high as 70,000. It has been found that the high potency of the best compound 7b that displays a K of 17 nM is due to an uncompetitive behavior toward mitoxantrone efflux and specific for that drug, compared to Hoechst 33342 efflux. Such property may be useful to target such anticancer drug efflux mediated by ABCG2. Finally, at a molecular level, an uncompetitive mechanism by which substrate promotes inhibitor binding implies that at least 2 ligands should bind simultaneously to the drug-binding pocket of ABCG2.
多药耐药膜泵通过输出广泛的结构多样的药物来降低化疗的疗效。在这里，为了利用人乳腺癌耐药蛋白 (BCRP/ABCG2) 的多特异性和该泵的二聚体性质，从单体α,β-不饱和酮 4b 和酚类衍生物 5a 设计了新的二聚吲哚并吲哚基抑制剂。合成了 18 个同/杂二聚体库。同二聚化将抑制效力从亚微摩尔范围转移到纳米摩尔范围，与存在由 2-6 个亚甲基长的连接子连接的 5a 相关。非毒性的最佳二聚体显示出高达 70,000 的治疗比。已经发现，具有 17 nM K 值的最佳化合物 7b 的高效力是由于其对米托蒽醌外排的非竞争性行为，并且与 Hoechst 33342 外排相比，该药物具有特异性。这种特性可能有助于针对由 ABCG2 介导的此类抗癌药物外排。最后，在分子水平上，底物促进抑制剂结合的非竞争性机制意味着至少应同时有 2 个配体结合到 ABCG2 的药物结合口袋中。
