Abstract
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.
Highlights
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-substituted2-oxoindolin-1-yl)-N’-(2-oxoindolin-3-ylidene)acetohydrazides (5)
We examined the effects of 4f, 4h, 4n, 4o, 4p, and PAC-1 on cell cycles at 50 μM
The first step was a nucleophilic substitution between 2-oxoindoline derivatives and ethyl chloroacetate with the presence of potassium carbonate with a catalytic amount of KI in acetone to afford the selectively N-alkylated intermediate esters (2)
Summary
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-substituted2-oxoindolin-1-yl)-N’-(2-oxoindolin-3-ylidene)acetohydrazides (5). neuroblastoma[10], breast cancer[11], lung carcinoma[12], hepatocellular c arcinoma[13], lymphoma and Hodgkin’s Disease[14]) Due to their overexpression in cancer cells, it is well established that targeting caspases would be more advantageous over inhibiting other apoptotic p roteins[9]. We recently reported several series of 4-oxoquinazoline-based acetohydrazides (I, II) which incorporated the N-acylhydrazone functionality and found many compounds with potent procaspase-3 activating activity as well as strong antitumor cytotoxicity[19,20] Encouraged by these results, in this investigation we expand our design to compounds series III and IV bearing 2-oxoindoline ring. This paper describes the results obtained from synthesis, bioevaluation of these novel compounds
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