Arylacetamides exhibit antiproliferative effects on non-transformed mammalian and vegetal cells and toxicity on crustaceans and fish embryos.

IF 2.1 4区 医学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Kátia da Conceição Machado, Jurandy do Nascimento Silva, Débora Caroline do Nascimento Rodrigues, Stefânia Neiva Lavorato, João Marcelo de Castro E Sousa, Ana Amélia de Carvalho Melo-Cavalcante, Patrícia Canteri de Souza, Paulo César Meletti, Diego Sousa Moura, José Roberto de Oliveira Ferreira, Cesar Koppe Grisolia, Ricardo José Alves, Paulo Michel Pinheiro Ferreira
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Abstract

Non-clinical steps for development, validation and biosafety of new medicines and products comprises studies on cells, proteins, and animals. Herein, we evaluated the toxic activity of antitumoral 2-chloro-N-arylacetamides on eukaryotic dividing cells and animal replacement models. Firstly, the cytotoxicity of chloro (compound 2), bromo (compound 3) and nitro (compound 4) acetamides was analyzed by fluorescent assays in fibroblasts. Next, toxicity was evaluated on Allium cepa meristematic cells and 48h-living Artemia salina larvae. Finally, embryos of Danio rerio (zebrafish) were exposed to the compound 2 (0.14 - 7.2 μg/mL) for 120 h exposure. All arylacetamides were cytotoxic on murine and human fibroblasts, with IC50 values ranging from 1.2 μg/mL (5.6 µM = compound 4 on L-929) to 4.9 μg/mL (24 µM = compound 2 on MRC-5 cells), respectively, and inhibited root growth from 10 to 100 µg/mL, corroborated by mitotic index reduction and cell cycle arrest in interphase (p < 0.05) without clastogenic injuries. Compound 2 showed time- and concentration-dependent killing effects on zebrafish embryos. Its 24 h-acute toxicity at higher concentrations (1.93 and 7.2 μg/mL with 90% and 100% death) corroborated toxicity on aquatic A. salina organisms. After 96 h exposure at 0.52 μg/mL (2.55 µM), almost 100% of the embryos showed more than one lethal/sublethal morphological abnormality (p < 0.05). Then, all arylacetamides showed unspecific toxic effects, mainly the halogenated electrophile chloroacetamide. They present strong antimitotic action on vertebrate and vegetal cells, although such antiproliferative activity does not seem to be directly related to chromosomal damage inductions.

芳酰乙酰胺对未转化的哺乳动物和植物细胞具有抗增殖作用,对甲壳类动物和鱼类胚胎具有毒性。
新药和产品的开发、验证和生物安全性的非临床步骤包括对细胞、蛋白质和动物的研究。在此,我们评估了抗肿瘤2-氯- n -芳基乙酰酰胺对真核分裂细胞和动物替代模型的毒性活性。首先,采用荧光法分析氯(化合物2)、溴(化合物3)和硝基(化合物4)乙酰酰胺对成纤维细胞的细胞毒性。其次,对大蒜分生组织细胞和48小时活的盐渍蒿幼虫进行毒性评价。最后,将斑马鱼胚胎暴露于化合物2 (0.14 ~ 7.2 μg/mL)中120 h。所有芳基乙酰酰胺对小鼠和人成纤维细胞均有细胞毒性,IC50值分别为1.2 μg/mL (L-929上5.6 μ M =化合物4)至4.9 μg/mL (MRC-5细胞上24 μ M =化合物2),抑制根生长10 ~ 100 μg/mL,有丝分裂指数降低和间期细胞周期阻滞证实了这一点(p 2显示出对斑马鱼胚胎的杀伤作用随时间和浓度的变化)。其在较高浓度下的24 h急性毒性(1.93和7.2 μg/mL,死亡率分别为90%和100%)证实了对水生盐藻生物的毒性。在0.52 μg/mL(2.55µM)浓度下暴露96 h后,几乎100%的胚胎表现出一种以上的致死性/亚致死性形态异常
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来源期刊
Drug and Chemical Toxicology
Drug and Chemical Toxicology 医学-毒理学
CiteScore
6.00
自引率
3.80%
发文量
99
审稿时长
3 months
期刊介绍: Drug and Chemical Toxicology publishes full-length research papers, review articles and short communications that encompass a broad spectrum of toxicological data surrounding risk assessment and harmful exposure. Manuscripts are considered according to their relevance to the journal. Topics include both descriptive and mechanics research that illustrates the risk assessment implications of exposure to toxic agents. Examples of suitable topics include toxicological studies, which are structural examinations on the effects of dose, metabolism, and statistical or mechanism-based approaches to risk assessment. New findings and methods, along with safety evaluations, are also acceptable. Special issues may be reserved to publish symposium summaries, reviews in toxicology, and overviews of the practical interpretation and application of toxicological data.
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