CHEMICAL DECOMPOSITION OF ALKYLATING NITROSO COMPOUNDS

烷基化亚硝基化合物的化学分解

• 批准号: 3169622
• 负责人: DAVID E JENSEN
• 金额: $ 10.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-02-01 至 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3169622
• 关键词: WI38 cell; blood chemistry; cell population study; cellular oncology; chemical carcinogen; chemical carcinogenesis; cimetidine; high performance liquid chromatography; methylation; nitrosamines; radiotracer; urinalysis

The widely used drug cimetidine ("Tagamet") can be nitrosated in the presence of nitrite and under mild acid conditions to form a compound, nitrosocimetidine (NC), which has a chemical structure very similar to those of the mutagens and laboratory carcinogens N-methyl-N feet-nitro-N-nitrosoguanidine (MNNG) and methylnitrosourea (MNU). NC has given positive indications in several short-term tests for possible carcinogenic activity and is capable fo methylating DNA in a manner identical to that of MNNG and of MNU. Nevertheless, NC has been found to be a weak or noncarcinogen and to be very poor at modifying DNA in vivo. Our experiments have indicated that NC, like MNNG, decomposes very rapidly in the presence of thiol compounds. Much of this decomposition is denitrosation. The compound also rapidly decomposes in isolated whole blood and in purified hemoglobin solutions. In both cases denitrosation predominates. We have discovered that incubation of NC with hemoglobin produces nitrosylhemoglobin and have demonstrated hemoglobin cysteine residue involvement. We suspect that hemoglobin-mediated denitrosation limits the in vivo activity of NC. Our hypothesis is that the strong electron-withdrawing cyano group in NC promotes, in the presence of thiol, both decomposition to produce a methylating species and decomposition by denitrosation. Denitrosation predominates. MNNG also has an electron-withdrawing group, the nitro moiety, and in this case methylating species production prevails. To test our supposition and to establish the range of compounds over which the denitrosation phenomenon might have effect, we propose to synthesize a series of 1,3-dimethyl-1-nitroso compounds which contain substituents with different electron-withdrawing capacity. We will establish their in vitro degradation properties and their in vivo DNA alkylating potential. We will also continue our study of nitrosylhemoglobin formation. Finally we propose to use this same series of compounds, which we anticipate will have differential thiol sensitivity, to determine the role of intracellular glutathione in nitroso compound activation, inactivation and reactive intermediate scavenging.

广泛使用的药物西咪替丁（“Tagamet”）可以在 在亚硝酸盐存在下并在温和的酸性条件下形成化合物， 亚硝基胍（NC），其化学结构与 诱变剂和实验室致癌物N-甲基-N 硝基亚硝基胍（MNNG）和甲基亚硝基脲（MNU）。 提名委员会已 在几次短期测试中， 致癌活性，并能够甲基化DNA的方式， 与MNNG和MNU的相同。 然而，NC被发现 是一种弱的或非致癌的物质，并且在体内修饰DNA方面非常差。 我们的实验表明，NC，像MNNG，分解非常迅速 在硫醇化合物的存在下。 大部分的分解是 脱亚硝化 该化合物也迅速分解成孤立的整体 血液和纯化的血红蛋白溶液中。 在这两种情况下， 占主导地位。 我们已经发现NC与血红蛋白的孵育 产生亚硝基血红蛋白，并已证明血红蛋白半胱氨酸 残留物参与。 我们怀疑血红蛋白介导的去亚硝化作用 限制了NC的体内活性。 我们的假设是强者 NC中的吸电子氰基，在硫醇存在下， 既分解产生甲基化物质， 脱亚硝化 反硝化作用占主导地位。 MNNG也有一个 吸电子基团，硝基部分，在这种情况下甲基化 物种生产占主导地位。 为了验证我们的假设， 脱亚硝化现象可能具有的化合物范围 效果，我们建议合成一系列的1，3-二甲基-1-亚硝基 含有不同吸电子取代基的化合物 容量 我们将确定其体外降解特性， 它们的体内DNA烷基化潜力。 我们亦会继续研究 亚硝基血红蛋白形成。 最后，我们建议使用同一系列 化合物，我们预计将有不同的硫醇敏感性， 确定细胞内谷胱甘肽在亚硝基化合物中的作用 活化、失活和活性中间体清除。