海洋萘醌-萘酚衍生物作为潜在抗癌药的设计、合成与生物学评价
Design, synthesis and biological evaluation of marine naphthoquinone-naphthol derivatives as potential anticancer agents
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影响因子:5.4
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
DOI:
10.1080/14756366.2024.2412865
摘要
1'-羟基-4',8,8'-三甲氧基-[2,2'-联萘-1,4-酮]（化合物5）是一种最近在海洋真菌中发现的次级代谢产物，显示出有希望的细胞毒性和抗癌潜力。然而，关于其衍生物的抗癌活性及其生物机制的研究仍有限。在此，我们设计、合成了一系列新型萘醌-萘酚衍生物，并评估其对不同来源癌细胞的抗癌活性。其中，化合物13在酮基的邻位引入氧丙基基团后，表现出对HCT116、PC9和A549细胞最强的抑制作用，与化合物5相比，IC50值分别从5.27降至1.18 μM（增加4.5倍）、6.98降至0.57 μM（增加12倍）和5.88降至2.25 μM（增加2.6倍）。进一步的机制研究显示，化合物13通过上调裂解型半胱天冬酶-3的表达和下调Bcl-2蛋白，显著诱导细胞凋亡，同时通过抑制EGFR/PI3K/Akt信号通路，抑制HCT116和PC9细胞的增殖。这些发现表明，该新型萘醌-萘酚衍生物具有潜在的抗癌药物开发价值。
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.