量子力学评估尼托胺功效的量子力学评估
Sriman De1, Bishnu Thapa2, Fareed Bhasha Sayyed1
1Synthetic Molecule Design and Development, Eli Lilly Services India Pvt Ltd, Devarabeesanahalli , Bengaluru 560103, India.
Chemical research in toxicology
|May 28, 2024
概括
量子力学 (QM) 建模通过分析反应性来预测尼트로胺的致癌性. 这种方法有助于估计新型尼托胺杂质的可接受摄入量 (AI),补充监管框架.
科学领域:
- 计算化学的计算化学
- 毒理学 毒理学 毒理学
- 药用化学 医学化学
背景情况:
- 亚胺是由于其强烈的致癌性质而引起关注的一类化合物.
- 新型尼托胺药物物质相关杂质 (NDSRI) 需要对致癌性的风险评估.
- 目前的监管指导要求将尼托胺限制在毒理学上令人担忧的值 (1.5微克/天) 以下.
研究的目的:
- 利用量子力学 (QM) 分析来理解罗斯胺致癌性的结构-反应性关系.
- 预测缺乏特定致癌性数据的NDSRI的致癌性.
- 为了将基于QM的预测与致癌潜力表征方法 (CPCA) 框架进行比较.
主要方法:
- 量子力学 (QM) 计算以确定关键代谢途径的激活能量.
- 分析多种尼胺结构,包括N-酸盐罗利丁,皮佩里丁,皮佩拉辛,形态素,形素,芳香和酸盐尼胺.
- 将QM结果与CPCA框架用于估计可接受摄入量 (AI) 的比较.
主要成果:
- 通过QM建模,通过代谢激活通路的激活能量,确定了尼特罗斯胺功效的趋势.
- 该研究发现,与QM预测相比,CPCA低估或高估AI的情况.
- 质量管理模型提供了一种更具分析性的方法来估计NDSRI的AI,特别是当CPCA表明高强度时.
结论:
- 对于对尼特罗斯胺代谢 (例如,α-氧化,水解,DNA相互作用) 的综合机理性理解对于预测效果至关重要.
- 质量管理建模提供了一种有价值的分析工具,可以为新型NDSRI改进AI估计.
- 这项工作支持和加强了CPCA等现有的监管框架,用于管理胺杂物.
相关概念视频
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Secondary amines react with nitrous acid to form N-nitrosamines, as depicted in Figure 1. Nitrous acid, a weak and unstable acid, is formed in situ from an aqueous solution of sodium nitrite and strong acids, such as hydrochloric acid or sulfuric acid, in cold conditions. In the presence of an acid, the nitrous acid gets protonated. The subsequent loss of water results in the formation of the electrophile known as nitrosonium ion.
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The nitrous acid is unstable. Hence, it is formed in situ from a solution of sodium nitrite and cold aqueous acids such as hydrochloric or sulfuric acid. In an acidic solution, the –OH group of nitrous acid undergoes protonation to give oxonium ion, followed by...
The nitrous acid is unstable. Hence, it is formed in situ from a solution of sodium nitrite and cold aqueous acids such as hydrochloric or sulfuric acid. In an acidic solution, the –OH group of nitrous acid undergoes protonation to give oxonium ion, followed by...
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Nitrous acid is a relatively weak and unstable acid prepared in situ by the reaction of sodium nitrite and cold, dilute hydrochloric acid. In an acidic solution, the nitrous acid undergoes protonation when it loses water to form a nitrosonium ion—an electrophile. Nitrous acid reacts with primary amines to give diazonium salts. The reaction is called diazotization of primary amines.
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Many organic, inorganic, and biological molecules contain spin-half nuclei such as nitrogen-15, fluorine-19, and phosphorus-31. As a result, NMR studies of these nuclei have found extensive applications in chemical and biological research.
While fluorine-19 and phosphorous-31 have high natural abundances (100%) and positive gyromagnetic ratios, nitrogen-15 has a low natural abundance and a negative gyromagnetic ratio. However, nitrogen-15 is still preferred over nitrogen-14 (which has a...
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The concept of rate-determining step can be understood from the analogy of a 4-lane freeway with a short-stretch of traffic-bottleneck caused due to...
In a multistep reaction mechanism, one of the elementary steps progresses significantly slower than the others. This slowest step is called the rate-limiting step (or rate-determining step). A reaction cannot proceed faster than its slowest step, and hence, the rate-determining step limits the overall reaction rate.
The concept of rate-determining step can be understood from the analogy of a 4-lane freeway with a short-stretch of traffic-bottleneck caused due to...
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