萘-1,4-二酮类似物作为抗癌剂的设计、合成及生物学评价
Design, synthesis and biological evaluation of naphthalene-1,4-dione analogues as anticancer agents.
作者信息
Cheng Yao, Yu Tsz Tin, Olzomer Ellen M, Beretta Martina, Katen Alice, Su Jacky, Jones John Patrick, Black David StC, Hoehn Kyle L, Byrne Frances L, Kumar Naresh
机构信息
School of Chemistry, University of New South Wales Sydney NSW 2052 Australia
School of Biotechnology and Biomolecular Sciences, University of New South Wales Sydney NSW 2052 Australia
出版信息
RSC Med Chem. 2025 Mar 19. doi: 10.1039/d4md00987h.
The increased metabolism of glucose aerobic glycolysis, known as the Warburg effect, is a hallmark of most cancers. Identifying molecules that disrupt the Warburg effect may allow for selective cytotoxicity towards cancer cells and reduce side effects compared to current chemotherapy agents. Our initial hit compound, BH10, which potentially targets Kelch-like ECH-associated protein 1 (Keap1), increased oxygen consumption rate and displayed increased cytotoxicity towards cancer cells over normal cells . In this project, a library of analogues based on the BH10 scaffold was prepared with the aim of improving potency and cancer-cell specificity. Among these analogues, several compounds showed notable potency, with activity (IC) observed around 1 μM. However, when considering selectivity, the imidazole derivative, compound 44, exhibited the most optimal balance, achieving an IC of 6.4 μM and selectivity ratio of 3.6 which indicates greater toxicity to cancer cells normal cells.
葡萄糖有氧糖酵解代谢增加，即所谓的瓦伯格效应，是大多数癌症的一个标志。识别破坏瓦伯格效应的分子可能会实现对癌细胞的选择性细胞毒性，并与目前的化疗药物相比减少副作用。我们最初的命中化合物BH10可能靶向 Kelch样ECH相关蛋白1（Keap1），它提高了氧消耗率，并且对癌细胞显示出比对正常细胞更高的细胞毒性。在这个项目中，制备了一个基于BH10支架的类似物库，目的是提高效力和癌细胞特异性。在这些类似物中，几种化合物显示出显著的效力，活性（IC）在1μM左右被观察到。然而，在考虑选择性时，咪唑衍生物化合物44表现出最理想的平衡，实现了6.4μM的IC和3.6的选择性比率，这表明对癌细胞的毒性大于对正常细胞的毒性。
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