Orally active antioxidative copper(II) aspirinate: synthesis, structure characterization, superoxide scavenging activity, and in vitro and in vivo antioxidative evaluations.
Ever since it was proposed that reactive oxygen species (ROS) are involved in the pathogeneses of various diseases, superoxide dismutase (SOD)-mimetic complexes have been intensively studied. We prepared copper(II) aspirinate [Cu2(asp)4] from Cu(II) and aspirin, which has been in use for many years as an antipyretic, an analgesic, and an anti-inflammatory agent. However, Cu2(asp)4 has been found to have additional activities, including anti-inflammatory, antiulcer, anti-ischemic/reperfusion agent, anticancer, antimutagenic, and antimicrobial activities. The activity of copper salicylate [Cu(sal)2] was also compared with that of Cu2(asp)4. The structure of the Cu2(asp)4 was determined using X-ray structure analysis. Its SOD-mimetic activity was determined using cytochrome c, electron spin resonance (ESR) spectroscopy, and ESR spin trap methods. The activity of Cu2(asp)4 was slightly greater than CuSO4 and copper acetate [Cu(ace)2] and slightly less than that of Cu(sal)2. The in vitro antioxidant activity, evaluated in human epithelial or transformed neoplastic keratinocyte cells, HaCaT, and normal dermal fibroblasts in terms of cell survival following ultraviolet B (UVB) irradiation, was significantly increased in the presence of Cu2(asp)4, Cu(sal)2, and CuSO4. Further, ROS generation following UVA irradiation in the skin of hairless mice following oral treatment with Cu2(asp)4 for three consecutive days was significantly suppressed compared to the vehicle- or Cu(ace)2-treated mice. On the basis of these results, Cu2(asp)4 was observed to be a potent antioxidative compound possessing antioxidative activity in biological systems. In conclusion, Cu2(asp)4 is a potent antioxidative agent that may be useful for future treatment of diseases resulting from ROS.
Fujimori
T
T
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nacauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan.
Yamada
S
S
Yasui
H
H
Sakurai
H
H
In
Y
Y
Ishida
T
T
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D019327:Copper Sulfate / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004847:Epithelial Cells / Q000187:drug effects; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism; D014466:Ultraviolet Rays
D016166:Free Radical Scavengers; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D012459:Salicylates; C507908:copper(II) aspirinate; D013481:Superoxides; C025564:copper salicylate complex; D019327:Copper Sulfate