Dipartimento di Scienze e Technologie Biologiche Chimiche e Farmaceutiche "STEBICEF" - University of Palermo, Via Archirafi - 32, 90123, Palermo, Italy.
Dipartimento di Scienze e Technologie Biologiche Chimiche e Farmaceutiche "STEBICEF" - University of Palermo, Via Archirafi - 32, 90123, Palermo, Italy.
Eur J Med Chem. 2021 Aug 5;220:113555. doi: 10.1016/j.ejmech.2021.113555. Epub 2021 May 24.
Quinoline is one of the most important and versatile nitrogen heterocycles embodied in several biologically active molecules. Within the numerous quinolines developed as antiproliferative agents, this review is focused on compounds interfering with DNA structure or with proteins/enzymes involved in the regulation of double helix functional processes. In this light, a special focus is given to the quinoline compounds, acting with classical/well-known mechanisms of action (DNA intercalators or Topoisomerase inhibitors). In particular, the quinoline drugs amsacrine and camptothecin (CPT) have been studied as key lead compounds for the development of new agents with improved PK and tolerability properties. Moreover, notable attention has been paid to the quinoline molecules, which are able to interfere with emerging targets involved in cancer progression, as G-quadruplexes or the epigenetic ones (e.g.: histone deacetylase, DNA and histones methyltransferase). The antiproliferative and the enzymatic inhibition data of the reviewed compounds have been analyzed. Furthermore, concerning the SAR (structure-activity relationship) aspects, the most recurrent ligand-protein interactions are summarized, underling the structural requirements for each kind of mechanism of action.
喹啉是几种具有生物活性的分子中最重要和用途最广泛的氮杂环之一。在作为抗增殖剂开发的众多喹啉化合物中，本综述重点关注干扰 DNA 结构或与调节双螺旋功能过程相关的蛋白质/酶的化合物。在这方面，特别关注喹啉化合物，其作用具有经典/众所周知的作用机制（DNA 插入剂或拓扑异构酶抑制剂）。特别地，吖啶酮和喜树碱（CPT）等喹啉类药物已被研究为开发具有改善 PK 和耐受性特性的新型药物的关键先导化合物。此外，还特别关注能够干扰癌症进展中涉及的新兴靶标的喹啉分子，如 G-四链体或表观遗传靶标（例如：组蛋白去乙酰化酶、DNA 和组蛋白甲基转移酶）。分析了综述化合物的抗增殖和酶抑制数据。此外，关于 SAR（构效关系）方面，总结了最常见的配体-蛋白质相互作用，强调了每种作用机制的结构要求。
