Abstract：
Although the presence of nitro groups in chemicals can be recognized as structural alerts for mutagenicity and carcinogenicity, nitroaromatic compounds have attracted considerable interest as a class of agents that can serve as source of potential new anticancer agents. In the present study, the in vitro cytotoxicity, genotoxicity, and mutagenicity of three synthetic ortho-nitrobenzyl derivatives (named ON-1, ON-2 and ON-3) were evaluated by employing human breast and ovarian cancer cell lines. A series of biological assays was carried out with and without metabolic activation. Complementarily, computational predictions of the pharmacokinetic properties and druglikeness of the compounds were performed in the Swiss ADME platform. The MTT assay showed that the compounds selectively affected selectively the cell viability of cancer cells in comparison with a nontumoral cell line. Additionally, the metabolic activation enhanced cytotoxicity, and the compounds affected cell survival, as demonstrated by the clonogenic assay. The comet assay, the cytokinesis-block micronucleus assay, and the immunofluorescence of the γ-H2AX foci formation assay have that the compounds caused chromosomal damage to the cancer cells, with and without metabolic activation. The results obtained in the present study showed that the compounds assessed were genotoxic and mutagenic, inducing double-strand breaks in the DNA structure. The high selectivity indices observed for the compounds ON-2 and ON-3, especially after metabolic activation with the S9 fraction, must be highlighted. These experimental biological results, as well as the theoretical properties predicted for the compounds have shown that they are promising anticancer candidates to be exploited in additional studies.
摘要：
尽管化学品中硝基的存在可以被认为是致突变性和致癌性的结构警报，硝基芳香化合物作为一类可以作为潜在的新抗癌剂来源的药物已经引起了相当大的兴趣。在本研究中,体外细胞毒性，遗传毒性，通过使用人乳腺癌和卵巢癌细胞系评估了三种合成的邻硝基苄基衍生物（分别称为ON-1，ON-2和ON-3）的致突变性。在有和没有代谢活化的情况下进行一系列生物学测定。互补,在瑞士ADME平台中对化合物的药代动力学特性和药物相似度进行了计算预测.MTT分析显示，与非肿瘤细胞系相比，这些化合物选择性地影响癌细胞的细胞活力。此外,代谢激活增强了细胞毒性，这些化合物影响细胞存活，如克隆形成试验所证明的。彗星试验，胞质分裂阻断微核试验，和γ-H2AX病灶形成试验的免疫荧光表明，这些化合物对癌细胞造成了染色体损伤，有和没有代谢激活。本研究中获得的结果表明，所评估的化合物具有遗传毒性和致突变性，在DNA结构中诱导双链断裂。观察到化合物ON-2和ON-3的高选择性指数，特别是在用S9馏分进行代谢活化后，必须强调。这些实验生物学结果，以及预测的化合物的理论性质表明，它们是有希望在其他研究中开发的抗癌候选物。
