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. ? ? ? ? ? ?
| Jin, Hongxia; Randazzo, James; Zhang, Peng et al. (2010) Multifunctional antioxidants for the treatment of age-related diseases. J Med Chem 53:1117-27 |
