海洋萘酮衍生物的设计，合成和生物学评估作为潜在的抗癌剂
Design, synthesis and biological evaluation of marine naphthoquinone-naphthol derivatives as potential anticancer agents
影响因子:5.40000
分区:医学2区 / 生化与分子生物学2区 药物化学2区
发表日期:2024 Dec
作者:
Yujuan Li, Luyou Yelv, Xiaoqiu Wu, Ning Liu, Yamin Zhu
摘要
1'-Hydroxy-4'，8,8'-trimethoxy- [2,2'-Binaphthalene] -1,4-二酮（化合物5），最近在海洋真菌中发现的次生代谢物，证明了有希望的细胞毒性和抗癌潜力。但是，有关其衍生物的抗癌活性和生物学机制的知识仍然有限。在此，设计，合成和评估了一系列新型的萘醌萘醇衍生物，并评估了其针对不同起源癌细胞的抗癌活性。其中，在喹酮群的正位上具有氧丙酰基的化合物13对HCT116，PC9和A549细胞表现出最有效的抑制作用，IC50值从5.27降低至1.18μm（4.5倍增加），6.98至6.98至0.57μm（12-Fold升高），2.25-fold升高至25-88（2.6-FOLD）（2.6-FOLD）（2.6-FOLD），（2.25 Y8），（2.25 OR）（2.25 OR）（2.25 OR）（2.25 OR）（2.25 OR）（2.25 YS）与化合物5相比。进一步的机械研究表明，化合物13通过增加裂解的caspase-3的表达水平来显着诱导细胞凋亡，并通过下调EGFR/PI3K/AKT信号通路来减少Bcl-2蛋白质，从而抑制HCT116和PC9细胞的抑制。目前的发现表明，这种新型的萘酮萘酚衍生物可能是抗癌治疗铅的潜力。
Abstract
1'-Hydroxy-4',8,8'-trimethoxy-[2,2'-binaphthalene]-1,4-dione (compound 5), a secondary metabolite recently discovered in marine fungi, demonstrates promising cytotoxic and anticancer potential. However, knowledge regarding the anticancer activities and biological mechanisms of its derivatives remains limited. Herein, a series of novel naphthoquinone-naphthol derivatives were designed, synthesised, and evaluated for their anticancer activity against cancer cells of different origins. Among these, Compound 13, featuring an oxopropyl group at the ortho-position of quinone group, exhibited the most potent inhibitory effects on HCT116, PC9, and A549 cells, with IC50 values decreasing from 5.27 to 1.18 μM (4.5-fold increase), 6.98 to 0.57 μM (12-fold increase), and 5.88 to 2.25 μM (2.6-fold increase), respectively, compared to compound 5. Further mechanistic studies revealed that compound 13 significantly induced cell apoptosis by increasing the expression levels of cleaved caspase-3 and reducing Bcl-2 proteins through downregulating the EGFR/PI3K/Akt signalling pathway, leading to the inhibition of proliferation in HCT116 and PC9 cells. The present findings suggest this novel naphthoquinone-naphthol derivative may hold potential as an anticancer therapeutic lead.