PDF(Pubmed)
Abstract：
N-nitrosamines and nitrosamine drug substance related impurities (NDSRIs) became a critical topic for the development and safety of small molecule medicines following the withdrawal of various pharmaceutical products from the market. To assess the mutagenic and carcinogenic potential of different N-nitrosamines lacking robust carcinogenicity data, several approaches are in use including the published carcinogenic potency categorization approach (CPCA), the Enhanced Ames Test (EAT), in vivo mutagenicity studies as well as read-across to analogue molecules with robust carcinogenicity data. We employ quantum chemical calculations as a pivotal tool providing insights into the likelihood of reactive ion formation and subsequent DNA alkylation for a selection of molecules including e.g., carcinogenic N-nitrosopiperazine (NPZ), N-nitrosopiperidine (NPIP), together with N-nitrosodimethylamine (NDMA) as well as non-carcinogenic N-nitrosomethyl-tert-butylamine (NTBA) and bis (butan-2-yl) (nitros)amine (BBNA). In addition, a series of nitroso-methylaminopyridines is compared side-by-side. We draw comparisons between calculated reaction profiles for structures representing motifs common to NDSRIs and those of confirmed carcinogenic and non-carcinogenic molecules with in vivo data from cancer bioassays. Furthermore, our approach enables insights into reactivity and relative stability of intermediate species that can be formed upon activation of several nitrosamines. Most notably, we reveal consistent differences between the free energy profiles of carcinogenic and non-carcinogenic molecules. For the former, the intermediate diazonium ions mostly react, kinetically controlled, to the more stable DNA adducts and less to the water adducts via transition-states of similar heights. Non-carcinogenic molecules yield stable carbocations as intermediates that, thermodynamically controlled, more likely form the statistically preferred water adducts. In conclusion, our data confirm that quantum chemical calculations can contribute to a weight of evidence approach for the risk assessment of nitrosamines.
摘要：
N-亚硝胺和亚硝胺药物物质相关杂质(NDSRIs)在各种药物产品从市场撤出后成为小分子药物开发和安全性的关键主题。为了评估缺乏可靠致癌性数据的不同N-亚硝胺的诱变和致癌潜力，几种方法正在使用中，包括已发布的致癌效力分类方法(CPCA)，增强型艾姆斯测试(EAT)，体内诱变性研究以及对具有强大致癌性数据的类似物分子的阅读。我们采用量子化学计算作为关键工具，提供对反应离子形成和随后的DNA烷基化的可能性的见解，用于选择分子，包括例如，致癌的N-亚硝基哌嗪（NPZ），N-亚硝基哌啶(NPIP),以及N-亚硝基二甲胺（NDMA）以及非致癌性N-亚硝基甲基-叔丁胺（NTBA）和双（丁-2-基）（硝基）胺（BBNA）。此外,并列比较了一系列亚硝基甲基氨基吡啶。我们将代表NDSRI常见基序的结构的计算反应曲线与已确认的致癌和非致癌分子的反应曲线与来自癌症生物测定的体内数据进行比较。此外，我们的方法能够深入了解中间物质的反应性和相对稳定性，这些中间物质可以在几种亚硝胺活化后形成。最值得注意的是,我们揭示了致癌和非致癌分子的自由能之间的一致差异。对于前者,中间重氮离子大部分反应，动力学控制，通过相似高度的过渡态，更稳定的DNA加合物和更少的水加合物。非致癌分子产生稳定的碳阳离子作为中间体，热力学控制，更有可能形成统计上优选的水加合物。总之,我们的数据证实,量子化学计算有助于亚硝胺风险评估的证据权重法.
