Synthesis, Biological Evaluation, and Autophagy Mechanism of 12N-Substituted Sophoridinamines as Novel Anticancer Agents

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• 作者：Chongwen Bi ; Na Zhang ; Peng Yang ; Cheng Ye ; Yanxiang Wang ; Tianyun Fan ; Rongguang Shao ; Hongbin Deng ; Danqing Song
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：8
• 期：2
• 页码：245-250
• 全文大小：421K
• ISSN：1948-5875

文摘

A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure–activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N′-end could greatly enhance antiproliferation potency. Among them, compound 6b possessing a N′-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC₅₀ between 0.55 and 1.7 μM. The underlying mechanism of 6b against tumor cells is to block autophagic flux, mainly through neutralizing lysosomal acidity. Our results indicated that compound 6b is a potent lysosomal deacidification agent and is accordingly able to block autophagic flux and inhibit tumor cell growth.