CHEMICAL DECOMPOSITION OF ALKYLATING NITROSO COMPOUNDS

广泛使用的药物西咪替丁(泰格美)可以在 亚硝酸盐的存在和在温和的酸性条件下形成化合物， 亚硝咪替丁(NC)，其化学结构非常类似于 致突变剂和实验室致癌物N-甲基-N 甲基亚硝胺(MNU)和甲基亚硝胺(MNNG)。NC有 在几个短期测试中出现阳性迹象，可能 具有致癌活性，能够以一种方式使DNA甲基化 与MNNG和MNU相同。然而，NC已经被发现 是一种弱致癌物质或非致癌物质，在体内修饰DNA的能力很差。 我们的实验表明，NC和MNNG一样，分解得非常快 在硫醇化合物存在的情况下。这种分解的很大一部分是 反硝化。这种化合物也会在孤立的整体中迅速分解 血液和纯化的血红蛋白溶液中。在这两种情况下的脱氮 占主导地位。我们发现NC与血红蛋白的孵育 产生亚硝基血红蛋白，并显示出半胱氨酸的血红蛋白 残留物牵涉其中。我们怀疑血红蛋白介导的反硝化作用 限制了NC的体内活性。我们的假设是，强者 在硫醇存在下，NC中的吸电子氰基促进， 分解以产生甲基化物种和通过 反硝化。脱氮作用占主导地位。MNNG也有一个 吸电子基团，硝基部分，在这种情况下是甲基化 物种生产占上风。来检验我们的假设，并建立 脱氮现象可能具有的化合物范围 我们建议合成一系列1，3-二甲基-1-亚硝基 含有不同吸电子能力的取代基的化合物 容量。我们将确定它们的体外降解特性，并 它们在体内的DNA烷基化潜力。我们还将继续研究 亚硝基血红蛋白的形成。最后，我们建议使用相同的系列 我们预计这些化合物会对硫醇有不同的敏感性， 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。

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.