SynbioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.
Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia.
ChemMedChem. 2020 Dec 15;15(24):2477-2490. doi: 10.1002/cmdc.202000402. Epub 2020 Sep 21.
Nitroxoline, a well-known antimicrobial agent, has been identified in several independent studies, and on different molecular targets, as a promising candidate to be repurposed for cancer treatment. One specific target of interest concerns cathepsin B, a lysosomal peptidase involved in the degradation of the extracellular matrix (ECM), leading to tumor invasion, metastasis and angiogenesis. However, dedicated optimization of the nitroxoline core is needed to actually deliver a nitroxoline-based antitumor drug candidate. Within that context, 34 novel nitroxoline analogs were synthesized and evaluated for their relative cathepsin B inhibitory activity, their antiproliferative properties and their antimicrobial activity. More than twenty analogs were shown to exert a similar or even slightly higher cathepsin B inhibitory activity compared to nitroxoline. The implemented modifications of the nitroxoline scaffold and the resulting SAR information can form an eligible basis for further optimization toward more potent cathepsin B inhibitors in the quest for a clinical nitroxoline-based antitumor agent.
硝呋太尔，一种广为人知的抗菌剂，已在多项独立研究中被确定为一种有前途的候选药物，可用于癌症治疗的再利用。一个特别感兴趣的靶点是组织蛋白酶 B，一种溶酶体肽酶，参与细胞外基质（ECM）的降解，导致肿瘤侵袭、转移和血管生成。然而，需要对硝呋太尔的核心进行专门的优化，才能真正提供一种基于硝呋太尔的抗肿瘤候选药物。在这种情况下，合成了 34 种新型硝呋太尔类似物，并评估了它们对组织蛋白酶 B 的相对抑制活性、抗增殖特性和抗菌活性。与硝呋太尔相比，二十多种类似物显示出相似甚至稍高的组织蛋白酶 B 抑制活性。硝呋太尔骨架的修饰以及由此产生的 SAR 信息可以为进一步优化提供合格的基础，以获得更有效的组织蛋白酶 B 抑制剂，从而寻求基于硝呋太尔的抗肿瘤临床药物。
