Abstract

Pancreatic cancer (PC) is one of the deadliest carcinomas and in most cases, which are diagnosed with locally advanced or metastatic disease, current therapeutic options are highly unsatisfactory. Based on the anti-proliferative effects shown by nitroxoline, an old urinary antibacterial agent, we explored a large library of newly synthesised derivatives to unravel the importance of the OH moiety and pyridine ring of the parent compound. The new derivatives showed a valuable anti-proliferative effect and some displayed a greater effect as compared to nitroxoline against three pancreatic cancer cell lines with different genetic profiles. In particular, in silico pharmacokinetic data, clonogenicity assays and selectivity indexes of the most promising compounds showed several advantages for such derivatives, as compared to nitroxoline. Moreover, some of these novel compounds had stronger effects on cell viability and/or clonogenic capacity in PC cells as compared to erlotinib, a targeted agent approved for PC treatment.

摘要

胰腺癌（PC）是最致命的癌症之一，在大多数情况下，被诊断为局部晚期或转移性疾病，当前的治疗选择非常不令人满意。基于旧的尿液抗菌剂硝恶啉显示的抗增殖作用，我们探索了一个新合成的大型文库，以阐明母体化合物的OH部分和吡啶环的重要性。新的衍生物显示出有价值的抗增殖作用，并且与硝基氧代林相比，对三种具有不同遗传特征的胰腺癌细胞系显示出更大的作用。特别是计算机与硝氧索林相比，最有前途的化合物的药代动力学数据，克隆形成性测定和选择性指数显示了此类衍生物的多项优势。而且，与厄洛替尼（一种批准用于PC治疗的靶向药物）相比，其中一些新型化合物对PC细胞的细胞活力和/或克隆形成能力具有更强的影响。