Development of novel oxyl-radical quenching pharmacophores as drug candidates

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Development of antioxidants for the treatment of diseases associated with oxidative stress is being interested. In this research project, we intended to find novel oxyl-radical quenching pharmacophores as drug candidates.1.To utilize an antioxidant property of fullerene in organic solvent, we designed and synthesized water-soluble fullerenes, and found their effective reactive-oxygen-species(ROS)quenching activity in aqueous solvents. Water-soluble fullerene protected Parkinson's disease-like cell damages caused by MPP+.2.Planar catechin analogues, in which the catechol and chroman structure in catechin was constrained to be planar, were designed and synthesized. Their enhanced antioxidant property was established by ESR spectrometry. The effective protection of DNA-damage caused by ROS was confirmed by using plasmid DNA.3.Pyrazolone derivatives were designed and synthesized and their antioxidant properties were estimated. A derivative with an intramolecular hydrogen bonding was found … More to be an effective radical scavenger in ESR spin-trapping method.4.A new type of photoinduced nitric oxide(NO)donors was designed from nitrobenzene derivatives. Visible-light irradiation revealed efficient NO-releasing using ESR analysis and Griess assay. NO-releaseing activity was also confirmed in in vitro cell-level experiments.5.Structural basis for DNA-cleaving activity of resveratrol and its analogues were studied and the structure-activity relationship in DNA strand scission was characterized.6.Antioxidants with lipophilic substituent which can be located in cellular membrane were designed and synthesized. Their ROS-scavenging activity in membrane was evaluated by redox potential in liposome and by a protection from oxidative damage of phosphatidylserine moiety in liposomal membrane.These findings obtained by this research project will be useful for development of antioxidants for the treatment of diseases associated with oxidative stress. We are continuing further study on this research to find useful pharmacophores as antioxidants. Less