سنتز وارزیابی سمیت ترکیبات 3-اکسو بوتان آمید در برابر لنفوسیت های انسانی و میتوکندری های جدا شده از آنها.

رزاقی اصل, نیما and صیدی, عنایت اله and علیخانی, رادین and رضوانی, صبا and میری, رحیم and سلیمی, احمد (1396) سنتز وارزیابی سمیت ترکیبات 3-اکسو بوتان آمید در برابر لنفوسیت های انسانی و میتوکندری های جدا شده از آنها. Environmental Toxicology and Pharmacology ــ 51 . pp. 71-84. شاپا 1382-6689

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Official URL: http://www.sciencedirect.com/science/article/pii/S...


Synthesis and toxicity assessment of 3-oxobutanamides against human lymphocytes and isolated mitochondria

English Abstract

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 glutathione. Our results suggested that among assessed compounds, increased toxicity of compound 5 compared to other compounds could be likely attributed to the presence of bromine substituent in 5. Finally our findings proposed that using of antioxidants and mitochondrial/lysosomal protective agents could be beneficial in decreasing the toxicity of 5.

Item Type:Article
زبان سند : انگلیسی
نویسنده اول :نیما رزاقی اصل
نویسنده :عنایت اله صیدی
نویسنده :رادین علیخانی
نویسنده :صبا رضوانی
نویسنده :رحیم میری
نویسنده مسئول :احمد سلیمی
Additional Information:IF: 2.776 Indexed in: ISI, PubMed/Medline, Scopus
کلیدواژه ها (انگلیسی):3-Oxobutanamide derivatives; Human lymphocytes; Isolated mitochondria; Predictive toxicology
Subjects:QV pharmacology > QV 600 Toxicology
QV pharmacology
Divisions:School of Pharmacy > Department of Toxicology
School of Pharmacy > Department of Medicinal Chemistry
ID Code:9196
Deposited By: Dr Ahmad Salimi
Deposited On:19 Jul 1396 08:28
Last Modified:24 Jan 1401 10:57

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