Synthesis and Toxicity Assessment of 3-oxobutanamides against Human Lymphocytes and Isolated Mitochondria

Publication date: Available online 7 March 2017 Source:Environmental Toxicology and Pharmacology Author(s): Nima Razzaghi-Asl, Enaytollah Seydi, Radin Alikhani, Saba Rezvani, Ramin Miri, Ahmad Salimi To reduce costly late-phase compound scrubbing, there has been an increased focus on assessing compounds within in vitro assays that predict properties of human safety liabilities, before preclinical in vivo studies. The aim of our study was to answer the questions that whether the toxicity risk of a series of 3-oxobutanamide derivatives could be predicted by using of human lymphocytes and their isolated mitochondria. Using biochemical and flow cytometry assessments, we demonstrated that exposure of lymphocytes and isolated mitochondria to five 3-oxobutanamide derivatives (1–5) did not exhibit remarkable toxicity at low concentrations (50–500μM) but toxicity could be observed at high concentrations (1000 and 2000μM), particularly for N-(5-(4-bromophenyl)-3-isoxazolyl)-3-oxobutanamide (4) and N-(2-benzothiazolyl)-3-oxo butanamide (5). Compounds 4, 5 and partly N-(5-methyl-3-isoxazol yl)-3-oxo butanamide (1) also showed a marked cellular and mitochondrial toxicity while compound 5 displayed superior toxicity. Compound 5 induced cytotoxicity on human blood lymphocytes which was associated with the generation of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP) collapse, lysosomal membrane injury, lipid peroxidation and depletion of glu...
Source: Environmental Toxicology and Pharmacology - Category: Environmental Health Source Type: research