N-nitrosotolazoline: decomposition studies of a typical N-nitrosoimidazoline.
N-nitrosotolazoline: decomposition studies of a typical N-nitrosoimidazoline.
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DOI：
10.1021/tx700318k
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发表时间：
2008-01
影响因子：
4.1
通讯作者：
R. Loeppky;Jianzheng Shi
中科院分区：
文献类型：
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作者：
R. Loeppky;Jianzheng Shi
N-亚硝基妥拉唑啉（N-nitroso-2-benzylimidazoline）是一种典型的N-亚硝基咪唑啉类药物，容易与酸、亚硝酸或N-乙酰半胱氨酸水溶液反应，产生高度亲电的重氮离子，能够烷基化细胞亲核试剂。本文研究了N-亚硝基妥拉唑啉在无机酸和缓冲溶液中的酸水解动力学和机理。在酸性缓冲液中的分解机制，提出涉及快速可逆质子化的亚氨基氮原子，然后缓慢的一般碱催化添加H2O的2-碳的咪唑啉环，得到一个四面体中间体，这也是一个α-羟基亚硝胺。这种物质的快速分解产生重氮，其产物通过亲核攻击、消除和重排而衍生。一般的酸催化，氘溶剂动力学同位素效应（kH/kD = 1.15）和Δ S = -34 eu的观察支持所提出的机制。在30 ℃的磷酸盐缓冲液中，N-亚硝基妥拉唑啉的半衰期范围为5分钟（pH 3.5）至4小时（pH 6）。水解反应的主要产物是N-（2-羟乙基）苯乙酰胺。该产物和其他产物与反应性重氮离子中间体的形成一致。N-亚硝基妥拉唑林的亚硝酸化速度比妥拉唑林快50倍，并产生一系列由反应性重氮离子衍生的产物，但与底物水解产生的产物不同。N-乙酰半胱氨酸使N-亚硝基妥拉唑啉在pH 7下的分解速率增加25倍，并导致N-脱亚硝化和诱导分解产生亲电体。这些数据表明，N-亚硝基妥拉唑啉共享许多已知的直接作用诱变剂和致癌物的化学性质。
N-nitrosotolazoline ( N-nitroso-2-benzylimidazoline), a N-nitrosated drug typical of N-nitrosoimidazolines, reacts readily with aqueous acid, nitrous acid, or N-acetylcysteine to produce highly electrophilic diazonium ions capable of alkylating cellular nucleophiles. The kinetics and mechanism of the acidic hydrolytic decomposition of N-nitrosotolazoline have been determined in mineral acids and buffers. The mechanism of decomposition in acidic buffer is proposed to involve the rapid reversible protonation of the imino nitrogen atom followed by slow general base-catalyzed addition of H2O to the 2-carbon of the imidazoline ring to give a tetrahedral intermediate, which is also a alpha-hydroxynitrosamine. Rapid decomposition of this species gives rise to the diazonium from which the products are derived by nucleophilic attack, elimination, and rearrangement. The proposed mechanism is supported by the observations of general acid catalysis, a negligible deuterium solvent kinetic isotope effect ( kH/kD = 1.15) and delta S = -34 eu. In phosphate buffer at 30 degrees C, the half-lives of N-nitrosotolazoline range from 5 min at pH 3.5 to 4 h at pH 6. The main reaction product of the hydrolytic decomposition is N-(2-hydroxyethyl)phenylacetamide. This and other products are consistent with the formation of a reactive diazonium ion intermediate. N-nitrosotolazoline nitrosates 50 times more rapidly than tolazoline and results in a set of products derived from reactive diazonium ions but different from those produced from the hydrolytic decomposition of the substrate. N-acetylcysteine increases the decomposition rate of N-nitrosotolazoline by 25 times at pH 7 and results in both N-denitrosation and induced decomposition to produce electrophiles. These data suggest that N-nitrosotolazoline shares the chemical properties of many known direct-acting mutagens and carcinogens.