Design, synthesis and biological evaluation of the positional isomers of the galactose conjugates able to target hepatocellular carcinoma cells via ASGPR-mediated cellular uptake and cytotoxicity

文献类型： 外文期刊

第一作者： Ye, Wenchong

作者： Ye, Wenchong;Tang, Qun;Zhou, Tiantian;Fan, Chuangchuang;Wang, Xiaoyang;Wang, Chunmei;Zhang, Keyu;Zhou, Wen;Ye, Wenchong;Liao, Guochao;Ye, Wenchong;Zhou, Wen;Zhou, Cui

作者机构：

关键词： Glycoconjugates; ASGPR; Hepatocellular carcinoma; Galactose; Positional isomer

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：6.7； 五年影响因子：6.5 ）

ISSN： 0223-5234

年卷期： 2024 年 264 卷

页码：

收录情况： SCI

摘要： Galactose as a recognizing motif for asialoglycoprotein receptor (ASGPR) is a widely accepted vector to deliver cytotoxic agents in the therapy of hepatocellular carcinoma (HCC), however, the individual hydroxyl group of galactose (Gal) contributed to recognizing ASGPR is obscure and remains largely unanswered in the design of glycoconjugates. Herein, we designed and synthesized five positional isomers of Gal-anthocyanin Cy5.0 conjugates and three Gal-doxorubicin (Dox) isomers, respectively. The fluorescence intensity of Gal-Cy5.0 conjugates accumulated in cancer cells hinted the optimal modification sites of positions C2 and C6. Comparing to the cytotoxicity of other conjugates, C2-Gal-Dox (11) was the most potent. Moreover, Gal-Dox conjugates significantly the toxicity of Dox. A progressively lower internalization capacity and siRNA technology implied the cellular uptake and cytotoxicity directly related to the ASGPR expression level. Accordingly, position C2 of galactose may be the best substitution site via ASGPR mediation in the design of anti-HCC glycoconjugates.

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