CHEMISTRY OF BIOLOGICALLY RELEVANT QUINONE IMINES

苯醌亚胺是多种生物氧化的中间体。 系统，并假定这些物种扮演不同的角色。因此， 许多生物上重要的氨基儿茶酚胺的代谢 假定涉及苯二酚亚胺中间体和N-烷基苯酚 亚胺类药物可能与长期服用氯丙嗪的副作用有关 心理治疗。止痛药扑热息痛的毒性被归因于 一种新陈代谢形成的与细胞大分子结合的苯醌亚胺。 最近的研究从N-甲基椭圆剂中提取了一种苯醌亚胺 醋酸酯作为体内芳基化嘌呤核苷的中间体 核苷酸；因此，这种特殊的苯醌亚胺可能扮演着重要的角色 在椭圆烯的抗肿瘤活性中。 简单的苯醌亚胺以及参与生物效应的那些 上面提到的在用于它们的条件下通常非常不稳定 一代。这阻止了他们的孤立和更详细的研究 他们的化学、光谱学和生物学都受到了严格的控制 条件。因此，一种制备和分离苯二酮亚胺的方法 将允许对它们的化学和生物学进行深入研究。 我们的目标是开发非氧化生成苯二酚的方法。 亚胺在高度受控的条件下，在没有还原的情况下 苯醌亚胺、不定过量氧化剂、金属盐的形式 氧化，或大量的亲核试剂。这些反应 条件允许将苯二酚亚胺以纯形式分离出来 他们的化学和生物学可以在明确的定义下进行研究 条件。 初步结果表明，一种简单的苯二酚衍生物 通过我们开发的化学方法可以高产率地合成亚胺。 在拟议的研究中，这种方法将适用于 与生物相关的苯醌亚胺，如那些在生物中形成的 儿茶酚胺和9-羟基乙酸椭圆酯的氧化(见 上图)。在仔细定义的条件下对这些系统进行研究将 用生物学方法确定其反应产物和反应速率 重要的亲核分子。对苯二酚的光谱表征 合成的亚胺将允许评估激光拉曼光谱 活体化学对这些中间体在体内的化学的研究

Quinone imines are intermedites in the oxidation of a variety of biological systems, and various roles have been postulated for these species. Thus, the metabolism of a number of biologically important cathecholamines is postulated to involve quinone imine intermediates, and N-alkylated quinone imines may be involved in the side effects of long-term chloropromazine therapy. The toxicity of the analgesic paracetamol has been attributed to a metabolically formed quinone imine which binds cell macromolecules. Recent studies have invoked a quinone imine from N-methylellipticium acetate as the intermediate which arylates in vivo purine nucleosides and nucleotides; thus, this particular quinone imine may play an important role in the antitumor activity of ellipticene. Simple quinone imines as well as those involved in the biological effects noted above are usually quite unstable under the conditions used for their generation. This has prevented their isolation and a more detailed study of their chemistry, spectroscopy, and biology under carefully controlled conditions. Thus, a method for preparation and isolation of quinone imines would allow an in-depth study of their chemistry and biology. Our aim is to develop methods for the non-oxidative generation of quinone imines under highly controlled conditions, in the absence of the reduced form of the quinone imine, adventitious excess oxidant, metal salts from the oxidation, or large quantities of nucleophiles. These reaction conditions will allow the quinone imines to be isolated in pure form so that their chemistry and biology can be studied under well-defined conditions. Preliminary results have demonstrated that a simple derivative of quinone imines can be synthesized in good yield via chemistry we have developed. In the proposed research this approach will be adapted for the generation of biologically relevant quinone imines such as those formed in biological oxidation of catecholamines and 9-hydroxy-ellipticenium acetate (see above). A study of these systems under carefully defined conditions will establish the products and rates of their reactions with biologically important nucleophiles. Spectroscopic characterization of the quinone imines synthesized will allow evaluation of laser Raman spectroscopy for the study of the chemistry of these intermediates in vivo.