Quinone Roles in NO Reduction & Production Enhancements & Tumor-Targeted Toxicity

醌在 NO 还原中的作用

基本信息

批准号：
7288961
负责人：
ANTONIO E ALEGRIA
金额：
$ 20.13万
依托单位：
UNIVERSITY OF PUERTO RICO AT HUMACAO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2011-03-31
项目状态：
已结题

项目摘要

Quinones are important compounds used in antitumor therapy and other human illnesses. The common feature of these compounds is that these are prone to be reduced either chemically or enzymaticafly in biological media to produce reactive intermediates and products. Although efforts have been made in correlating redox potentials of these compounds with cytotoxicity, very little is known on how the environment affects the extent of production of reactive intermediates or products of these compounds in the presence of biologically relevant reducing agents. Our major aim is to understand the interrelated roles of environment and structure of these compounds and their intermediates, the semiquinones, in determining the extent of production of reactive oxygen and nitric oxide intermediates. By knowing this, an understanding of the cytotoxic action of these can be obtained and the design of more efficient drugs based on these types of compounds can be developed. Since semiquinone stabilization increases the rate of oxygen consumption in the presence of reducing agents we will now be studying the effect of metal chelation in orthosemiquinone stabilization and oxygen consumption. In contrast to previous years, and since the recognized most important macromolecule in determining both the formation and dead of tumor cells is the DNA molecule, we have now shifted our attention to DNA damaging reactions by cationic, neutral and anionic quinones in the presence and absence of reducing agents, and in the presence and absence of oxygen. Quinones are known to be reduced to the one-electron intermediate, the semiquinone, with the consequent production of reactive oxygen radicals after electron transfer to oxygen. In addition, semiquinones could also reduce nitric oxide to the nitrosyl ion with the consequent toxicity of this species.

醌是用于抗肿瘤治疗和其他人类疾病的重要化合物。常见的这些化合物的特点是它们很容易在化学或酶催化下被还原生产反应中间体和产品的生物介质。尽管已经做出了努力将这些化合物的氧化还原电位与细胞毒性联系起来，人们对如何将这些化合物的氧化还原电位与细胞毒性联系起来知之甚少。环境影响反应中间体或这些化合物的产物的生产程度生物相关还原剂的存在。我们的主要目标是了解相互关联的角色这些化合物及其中间体半醌的环境和结构，在确定活性氧和一氧化氮中间体的产生程度。知道了这一点，就明白了可以获得这些细胞毒性作用的信息，并基于这些类型设计更有效的药物可以开发出多种化合物。由于半醌稳定化会增加耗氧率在还原剂存在下，我们现在将研究金属螯合对邻半醌的影响稳定性和耗氧量。与往年相比，自从最受认可的决定肿瘤细胞形成和死亡的重要大分子是DNA分子，我们现在，我们将注意力转移到了阳离子、中性和阴离子醌在 DNA 损伤反应上。存在和不存在还原剂，以及存在和不存在氧气的情况下。醌类是已知被还原为单电子中间体半醌，随后产生电子转移到氧后产生活性氧自由基。此外，半醌还可以减少硝酸氧化成亚硝酰离子，从而产生该物质的毒性。