Bi Chongwen, Zhang Na, Yang Peng, Ye Cheng, Wang Yanxiang, Fan Tianyun, Shao Rongguang, Deng Hongbin, Song Danqing
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College , Beijing 100050, China.
ACS Med Chem Lett. 2017 Jan 5;8(2):245-250. doi: 10.1021/acsmedchemlett.6b00466. eCollection 2017 Feb 9.
A series of 12-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 '-end could greatly enhance antiproliferation potency. Among them, compound possessing a '-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC between 0.55 and 1.7 μM. The underlying mechanism of against tumor cells is to block autophagic flux, mainly through neutralizing lysosomal acidity. Our results indicated that compound is a potent lysosomal deacidification agent and is accordingly able to block autophagic flux and inhibit tumor cell growth.
合成了一系列12-取代槐定胺衍生物，并评估了它们对人HepG2肝癌细胞的细胞毒性活性。构效关系表明，在'-末端引入合适的亚芳基或芳基乙基可大大增强抗增殖能力。其中，具有'-三甲氧基苯基亚甲基的化合物对包括HepG2、白血病（K562）和乳腺癌（HMLE）在内的三种人类肿瘤细胞系表现出强大的抗增殖作用，IC在0.55至1.7μM之间。其抗肿瘤细胞的潜在机制是阻断自噬流，主要是通过中和溶酶体酸度。我们的结果表明，该化合物是一种有效的溶酶体去酸化剂，因此能够阻断自噬流并抑制肿瘤细胞生长。
