Sampangine (a Copyrine Alkaloid) Exerts Biological Activities through Cellular Redox Cycling of Its Quinone and Semiquinone Intermediates
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- 作者：Fakhri Mahdi ; J. Brian Morgan ; Wenlong Liu ; Ameeta K. Agarwal ; Mika B. Jekabsons ; Yang Liu ; Yu-Dong Zhou ; Dale G. Nagle
- 刊名：Journal of Natural Products
- 出版年：2015
- 出版时间：December 24, 2015
- 年：2015
- 卷：78
- 期：12
- 页码：3018-3023
- 全文大小：455K
- ISSN：1520-6025
文摘
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.