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.

中文翻译：

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具有强效组织蛋白酶 B 外肽酶抑制活性的新型硝基唑啉类似物的合成。

Nitroxoline 是一种众所周知的抗菌剂，已在几项独立研究和不同分子靶标中被确定为重新用于癌症治疗的有希望的候选药物。一个感兴趣的特定目标涉及组织蛋白酶 B，这是一种溶酶体肽酶，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，需要对硝基氧的核心进行专门优化，才能真正提供基于硝基氧的抗肿瘤候选药物。在这种情况下，合成了 34 种新的硝基氧杂环戊烷类似物，并评估了它们的相对组织蛋白酶 B 抑制活性、抗增殖特性和抗菌活性。与硝基氧嘧啶相比，超过 20 种类似物显示出类似或什至略高的组织蛋白酶 B 抑制活性。对硝唑啉支架的实施修改和由此产生的 SAR 信息可以形成一个合格的基础，以进一步优化更有效的组织蛋白酶 B 抑制剂，以寻求临床基于硝唑啉的抗肿瘤剂。