Aims: the main purpose of this study was to identify new selective antitumor agents.
Main methods: several hydrazonoyl chlorides (HCs) were synthesized and human tumor cell line viability was determined using the MTT assay. Tumor development was assessed using Ehrlich ascites carcinoma (EAC)-bearing mice.
Key findings: our results showed that 2-oxo-N-phenyl-2-(phenylamino)acetohydrazonoyl chloride (compound 4; CPD 4) and 2-oxo-2-(phenylamino)-N-(p-tolyl)acetohydrazonoyl chloride (CPD 5) were the most cytotoxic HCs to human cervical tumor HeLa (IC50: 20 and 25 μM for CPD 4 and 5 respectively), breast MCF7 (IC50: 29 and 34 μM for CPD 4 and 5 respectively) and colon HCT116 cancer cells (IC50: 26 and 25 μM for CPD 4 and 5 respectively) with the least cytotoxicity to human non-tumor CCD-18Co colon fibroblasts as well as murine splenocytes. The active compounds significantly inhibited colony formation as well as tumor development in EAC-bearing mice. We also observed that PTEN-deficient cells displayed greater sensitivity than cells expressing wild type PTEN. At the molecular level, comet and cell cycle analyses indicated that the active compounds generate DNA damage. In light of the PTEN-dependent sensitivity and genomic instability we examined the influence of HCs on the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) and the PI3K/AKT/mTOR pathway, which are each known to be synthetic lethal with PTEN. We found that both PNKP and the PI3K/AKT/mTOR pathway to be adversely affected by the HCs, which may partially account for their toxicity.
Significance: hydrazonoyl chlorides can be considered as hit compounds for the development of new antitumor agents.
Keywords: Ehrlich ascities carcinoma; Hydrazonoyl chlorides; PI3K/AKT/mTOR; PNKP; PTEN; Synthetic lethality.
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