Design, synthesis and evaluation of novel 2-oxoindoline-based acetohydrazides as antitumor agents

In our search for novel small molecules activating procaspase-3, we have designed and synthesized two series of novel ( E )- N' -arylidene-2-(2-oxoindolin-1-yl)acetohydrazides ( 4) and (Z)- 2-(5-substituted-2-oxoindolin-1-yl)- N' -(2-oxoindolin-3-ylidene)acetohydrazides ( 5) . Cytotoxic evaluation revealed that the compounds showed notable cytotoxicity toward three human cancer cell lines: colon cancer SW620, prostate cancer PC-3, and lung cancer NCI-H23. Especially, six compounds, including 4f–h and 4n–p , exhibited cytotoxicity equal or superior to positive control PAC-1, the first procaspase-3 activating compound. The most potent compound 4o was three- to five-fold more cytotoxic than PAC-1 in three cancer cell lines tested. Analysis of compounds effects on cell cycle and apoptosis demonstrated that the representative compounds 4f, 4h, 4n, 4o and 4p (especially 4o ) accumulated U937 cells in S phase and substantially induced late cellular apoptosis. The results show that compound 4o would serve as a template for further design and development of novel anticancer agents.