Development of multi-functional antioxidants for use in cataract and age-related macular degeneration.

摘要

Oxidative stress induced by free radicals, including reactive oxygen species (ROS), results from the age-related decrease of antioxidant defenses, accumulation of iron and/or copper, and generation of hydroxyl radicals through the Fenton reaction. Oxidative stress may lead to the formation and progression of diseases such as age-related macular degeneration (AMD) and age-related cataract formation. In order to prevent and/or delay these diseases, a series of eight compounds that could act as either free radical scavengers (FRS), metal chelators (CHL), or both (multi-functional) were synthesized. In this work, we used a combination of assays including the method of continuous variation (Job Plots), ESI-MS analysis, and in vitro cell culture assays to evaluate the compounds antioxidative capability. The compounds were then evaluated for their potential use in age-related ocular disorders by being screened in proof-of-concept in vivo models of cataractogenesis and retinal degeneration.;The results are summarized as follows: a) chelating compounds form complexes with iron, copper, and zinc, but not with either calcium or magnesium in stoichiometries consistent with their geometry; b) compounds ) bound in the relative order of copper > iron > zinc; c) compounds possessing the unique 2-amino-5-pyrimidinol FRS and/or piperazine-2,6-dione CHL moiety were able to protect cultured cells against peroxide- and Fenton-induced oxidative damage; d) oral administration of multi-functional compounds delayed cataracts caused by ionizing radiation and diabetes; e) multi-functional antioxidants reduced endoplasmic reticular stress in lens culture; f) oral administration of multi-functional compounds reduced the oxidative burden placed on the neural retina following exposure to bright light; and g) multi-functional compounds improved retinal function in a light-induced retinal damage model. The data from these proof-of-concept studies suggest that multi-functional compounds may be potential drug candidates that could delay and/or prevent the progression of age-related cataract and AMD.