Saudagar Prakash, Saha Pipas, Saikia Anil K, Dubey Vikash Kumar
Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati, India.
Eur J Pharm Biopharm. 2013 Nov;85(3 Pt A):569-77. doi: 10.1016/j.ejpb.2013.08.014. Epub 2013 Aug 31.
We report oxabicyclo[3.3.1]nonanones as inhibitors of key redox enzymes, trypanothione synthetase (TryS), and trypanothione reductase (TryR) of Leishmania. Further, detailed cellular effects of 4-(4,4,8-Trimethyl-7-oxo-3-oxabicyclo[3.3.1]non-2-yl)-benzoic acid methyl ester, a oxabicyclo[3.3.1]nonanones, on the parasite were investigated. As these compounds inhibit key redox enzymes (TryR amd TryS), treatment of these compounds resulted in increased reactive oxygen species (ROS), mitochondrial membrane damage, activation of caspase like proteases, and DNA damage that finally leads to apoptosis. Although the compound has modest IC50 value against parasite (4.9±0.4 μM), they identify a novel chemical space to design and develop drugs based on these compounds against the Leishmania parasite. This is first report of oxabicyclo[3.3.1]nonanones as antileishmanial.
我们报道了氧杂双环[3.3.1]壬酮作为利什曼原虫关键氧化还原酶——锥虫硫醇合成酶（TryS）和锥虫硫醇还原酶（TryR）的抑制剂。此外，还研究了氧杂双环[3.3.1]壬酮类化合物4-(4,4,8-三甲基-7-氧代-3-氧杂双环[3.3.1]壬-2-基)苯甲酸甲酯对该寄生虫的详细细胞效应。由于这些化合物抑制关键氧化还原酶（TryR和TryS），用这些化合物处理会导致活性氧（ROS）增加、线粒体膜损伤、类半胱天冬酶蛋白酶激活以及DNA损伤，最终导致细胞凋亡。尽管该化合物对寄生虫的半数抑制浓度（IC50）值适中（4.9±0.4 μM），但它们确定了一个新的化学空间，可基于这些化合物设计和开发抗利什曼原虫的药物。这是关于氧杂双环[3.3.1]壬酮作为抗利什曼原虫药物的首次报道。
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