title: Sampangine (a Copyrine Alkaloid) Exerts Biological Activities through Cellular Redox Cycling of Its Quinone and Semiquinone Intermediates.
abstract: The cananga tree alkaloid sampangine (1) has been extensively investigated for its antimicrobial and antitumor potential. Mechanistic studies have linked its biological activities to the reduction of cellular oxygen, the induction of reactive oxygen species (ROS), and alterations in heme biosynthesis. Based on the yeast gene deletion library screening results that indicated mitochondrial gene deletions enhanced the sensitivity to 1, the effects of 1 on cellular respiration were examined. Sampangine increased oxygen consumption rates in both yeast and human tumor cells. Mechanistic investigation indicated that 1 may have a modest uncoupling effect, but predominately acts by increasing oxygen consumption independent of mitochondrial complex IV. Sampangine thus appears to undergo redox cycling that may involve respiratory chain-dependent reduction to a semi-iminoquinone followed by oxidation and consequent superoxide production. Relatively high concentrations of 1 showed significant neurotoxicity in studies conducted with rat cerebellar granule neurons, indicating that sampangine use may be associated with potential neurotoxicity.
authors.forename: Fakhri
authors.initials: F
authors.lastname: Mahdi
authors.forename: J Brian
authors.initials: JB
authors.lastname: Morgan
authors.affiliation: School of Pharmacy, Hunan University of Chinese Medicine , Changsha, Hunan Province 410208, People's Republic of China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Liu
authors.forename: Ameeta K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: Mika B
authors.initials: MB
authors.lastname: Jekabsons
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Hunan University of Chinese Medicine , Changsha, Hunan Province 410208, People's Republic of China.
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016227:Benzoquinones; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D019069:Cell Respiration / Q000187:drug effects; D004579:Electron Transport; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D009287:Naphthyridines; D010084:Oxidation-Reduction; D010100:Oxygen; D011809:Quinones / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D013481:Superoxides / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000890:Anti-Infective Agents; D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D006576:Heterocyclic Compounds, 4 or More Rings; D009287:Naphthyridines; D011809:Quinones; D017382:Reactive Oxygen Species; C116897:iminoquinone; D013481:Superoxides; C004532:quinone; C121572:sampangine; D010100:Oxygen