Multifunctional Antioxidants as Anti-Cataract Agents

产品说明：该探索性建议旨在研究开发含有多功能抗氧化剂基团的新型抗白内障药物的可行性，所述抗氧化剂基团可以延迟各种白内障的进展，所述白内障是基于由许多不同的损伤引发的白内障在透镜浑浊化过程中具有一些共同的生化变化的概念。这些常见的生物化学变化之一是氧化。 扩展我们的初步观察，选择基于结构4-[4-（N，N-二甲基氨磺酰基）-哌嗪基]-2-甲基-嘧啶延迟糖尿病性白内障的形成，而不抑制实验确定的糖尿病性白内障形成的引发剂-高血糖症和山梨糖醇形成，该建议寻求将官能团引入1-N，N '-二甲基氨磺酰基-4-（2-嘧啶基）哌嗪，其将赋予化合物作为抗氧化剂/自由基清除剂和铁/铜螯合剂的额外能力。本研究的目的是探索这样一个概念，即含有多个功能性抗氧化基团的化合物通过多种机制的组合来抵消透镜中活性氧（ROS）的形成是可行的，并且这些化合物可以增强我们的先导化合物不仅延迟糖尿病性白内障形成而且延迟与氧化应激直接相关的其他白内障的能力。拟定研究应提供足够的初步数据，用于进一步研究，以确定具有降低ROS和氧化性组织损伤能力的强效药物是否可作为抗白内障药物，显著延迟或预防透镜浑浊化的进展，而与白内障形成的起始来源无关。这种抗白内障剂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，而且还可以显著降低美国、其他发达国家和发展中国家白内障手术日益增加的经济负担。此外，其潜在的预防作用可用于接受 玻璃体切除术，以防止随后的氧诱导核性白内障，并由未来的宇航员进行长期太空飞行，而不会增加视力丧失的风险。

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.