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Multifunctional Antioxidants as Anti-Cataract Agents

多功能抗氧化剂作为抗白内障药物

基本信息

批准号：
7229937
负责人：
PETER F KADOR
金额：
$ 21.41万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229937
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Antioxidants Astronauts Biochemical Biological Blindness Cataract Cataract Extraction Chelating Agents Chemicals Copper Data Deferoxamine Developed Countries Developing Countries Development Diabetes Mellitus Economic Burden Evaluation Event Free Radical Scavengers Free Radical Scavenging Future Hyperbaric Oxygen Hyperglycemia In Vitro Iron Lead Metals Nuclear Numbers Oxidative Stress Oxygen Patients Piperazines Process Production Property Pyrimidine Pyrimidines Radiation Radiation-Protective Agents Reaction Reactive Oxygen Species Reducing Agents Reporting Risk Solutions Sorbitol Source Space Flight Structure System Tissues Tocopherols United States Vitrectomy WR 77913 ascorbate base concept diabetic cataract functional group inhibitor/antagonist lens novel novel strategies oxidation pantethine piperazine piperidine prevent prophylactic tempol

项目摘要

DESCRIPTION: This exploratory proposal seeks to investigate the feasibility of developing novel anti-cataract agents containing multifunctional antioxidant groups that can delay the progression of various cataracts based on the concept that cataracts initiated by a number of different insults share some common biochemical changes during the process of lens opacification. One of these common biochemical changes is oxidation. Expanding on our preliminary observation that select compounds based on the structure 4-[4-(N,Ndimethylsulfamoyl)-piperazino]-2-methyl-pyrimidine delay diabetic cataract formation without inhibiting the experimentally established initiators of diabetic cataract formation -- hyperglycemia and sorbitol formation, this proposal seeks to incorporate functional groups into 1-N,N'-dimethylsulfamoyl-4-(2-pyrimidyl)piperazine that will give the compound the added ability to serve as an antioxidant/free radical scavenger and iron/copper chelator. The aims of this study are to explore the concept that compounds containing multiple functional antioxidant groups to counteract the formation of reactive oxygen species (ROS) in the lens by a combination of mechanisms is feasible and that these compounds may enhance the ability of our lead compound to not only delay diabetic cataract formation but other cataracts that are directly associated with oxidative stress. The proposed studies should provide adequate preliminary data for further studies to determine whether potent agents with the ability to reduce ROS and oxidative tissue damage can serve as anti-cataract agents that significantly delay or prevent the progression of lens opacification independent of the initiating source(s) of cataract formation. The successful development of such an anti-cataract agent could not only decrease the increasing world-wide problem of cataract blindness, but also significantly reduce the increasing economic burden of cataract surgery in the United States, other developed countries, and the developing world. .Moreover, its potential prophylactic action could be used in patients undergoing vitrectomy to prevent subsequent oxygen induced nuclear cataracts and by future astronauts to conduct long-term space flights without the increased risks of vision loss.

描述：这项探索性的建议旨在研究开发含有多功能抗氧化基的新型抗白内障药物的可行性，该药物可以延缓各种白内障的进展，基于这样的概念，即由多种不同的损伤引发的白内障在晶状体混浊过程中具有共同的生化变化。这些常见的生化变化之一是氧化。在我们初步观察的基础上，选择基于结构4-[4-(N，Ndimethylsulfamoyl)-piperazino]-2-methyl-pyrimidine)的化合物在不抑制糖尿病白内障形成的实验建立的引发剂-高血糖和山梨醇形成的情况下延迟糖尿病白内障的形成，这一建议寻求在1-N，N‘-dimethylsulfamoyl-4-(2-pyrimidyl)piperazine中加入官能团，这将使该化合物具有作为抗氧化剂/自由基清除剂和铁/铜螯合剂的额外能力。这项研究的目的是探索这样一个概念，即含有多种功能抗氧化剂基团的化合物通过多种机制的组合来对抗晶状体中活性氧物种(ROS)的形成是可行的，并且这些化合物可能会增强我们的先导化合物不仅延缓糖尿病白内障形成的能力，而且还可以延缓其他与氧化应激直接相关的白内障的形成。建议的研究应该为进一步的研究提供足够的初步数据，以确定具有降低ROS和氧化组织损伤能力的有效药物是否可以作为抗白内障药，显著延缓或防止晶状体混浊的进展，而不依赖于白内障形成的起始来源(S)。这种抗白内障药物的成功开发，不仅可以减少日益严重的世界性白内障失明问题，而且还可以显著减轻美国、其他发达国家和发展中国家日益增加的白内障手术的经济负担。此外，其潜在的预防作用可用于玻璃体切割术，以防止随后的氧气引起的核性白内障，以及未来宇航员进行长期太空飞行而不会增加视力丧失的风险。