3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: a lead tumor-specific cytotoxin which induces apoptosis and autophagy.
3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: a lead tumor-specific cytotoxin which induces apoptosis and autophagy.
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DOI：
10.1016/j.bmcl.2009.12.076
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发表时间：
2010-02
影响因子：
2.7
通讯作者：
U. Das;H. Sakagami;Qing Chu;Qintao Wang;M. Kawase;Ponniah Selvakumar;Rajendra K. Sharma;J. Dimmock
中科院分区：
文献类型：
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作者：
U. Das;H. Sakagami;Qing Chu;Qintao Wang;M. Kawase;Ponniah Selvakumar;Rajendra K. Sharma;J. Dimmock
多种3,5-双（苄基）-4-哌酮2-5的N-4-（2-氨基乙氧基）苯基羰基衍生物对人HL-60白血病细胞以及人HSC-2和HSC-4鳞状细胞癌具有显著的细胞毒性。总的来说，对HGF、HPC和HPLF正常细胞的毒性明显较低。当末端碱为morpholine时，选择性毒性最高。铅优化是基于发现具有(1)高细胞毒性的化合物，(2)对肿瘤的毒性大于正常细胞，以及(3)基于五法则的药物相似性。从产生的生物数据来看，5a是一种有前景的先导化合物，值得进一步开发。5a的作用方式包括诱导HL-60细胞凋亡，其中核体间DNA断裂和caspase-3活化。此外，5a可引起HSC-2细胞自噬。
A number of N-4-(2-aminoethoxy)phenylcarbonyl derivatives of various 3,5-bis(benzylidene)-4-piperidones 2–5 demonstrated noteworthy cytotoxic potencies towards human HL-60 leukemic cells as well as human HSC-2 and HSC-4 squamous cell carcinomas. In general, toxicity towards HGF, HPC, and HPLF normal cells was substantially lower. The highest selective toxicity was noted when the terminal base is morpholine. Lead optimization was based on finding compounds which had (i) high cytotoxic potencies, (ii) a greater toxicity to neoplasms than normal cells, and (iii) drug-likeness based on the rule of five. From the biodata generated, 5a evolved as a promising lead compound for further development. The mode of action of 5a included the induction of apoptosis in HL-60 cells in which internucleosomal DNA fragmentation and activation of caspase-3 was noted. In addition, 5a caused autophagy in HSC-2 cells.