Javiera Órdenes-Rojas, Paola Risco, José Ortega-Campos, Germán Barriga-González, Ana Liempi, U. Kemmerling, D. Gambino, L. Otero, Claudio Olea Azar, Esteban Rodríguez-Arce
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引用次数: 0
摘要
为了寻找一种更有效的化疗方法来治疗由克鲁斯锥虫寄生虫引起的南美锥虫病,使用金化合物可能是一种很有前景的方法。在这项工作中,研究了四种金(I)化合物 [AuCl(HL)](HL = 含有生物活性的 5-硝基呋喃硫代氨基脲)。这些化合物具有相同的化学结构,金属离子位于线性配位环境中,而硫代氨基脲则作为单齿配体。循环伏安法和电子自旋共振(ESR)研究表明,这些复合物可以通过还原硝基分子产生硝基阴离子自由基(NO2-)。在体外对这些化合物进行了评估,结果表明它们能抑制恙虫的胰母细胞形态和人的内皮形态细胞。所研究的金化合物对 T. cruzi 的活性在微摩尔范围内。与各自的生物活性配体相比,活性最强的化合物(IC50 约为 10 μM)显示出更强的抗寄生虫活性和适度的选择性。为了深入了解金化合物的抗寄生虫作用机制,我们通过 ESR 和荧光测量评估了金化合物在细胞内产生自由基的能力。对与复合物生物还原和氧化还原循环过程有关的 DMPO(5,5-二甲基-1-吡咯啉-N-氧化物)自旋加合物进行了表征。证实了对 T. cruzi 的潜在氧化应激机制。
Mechanism of Anti-Trypanosoma cruzi Action of Gold(I) Compounds: A Theoretical and Experimental Approach
In the search for a more effective chemotherapy for the treatment of Chagas’ disease, caused by Trypanosoma cruzi parasite, the use of gold compounds may be a promising approach. In this work, four gold(I) compounds [AuCl(HL)], (HL = bioactive 5-nitrofuryl containing thiosemicarbazones) were studied. The compounds were theoretically characterized, showing identical chemical structures with the metal ion located in a linear coordination environment and the thiosemicarbazones acting as monodentate ligands. Cyclic voltammetry and Electron Spin Resonance (ESR) studies demonstrated that the complexes could generate the nitro anion radical (NO2−) by reduction of the nitro moiety. The compounds were evaluated in vitro on the trypomastigote form of T. cruzi and human cells of endothelial morphology. The gold compounds studied showed activity in the micromolar range against T. cruzi. The most active compounds (IC50 of around 10 μM) showed an enhancement of the antiparasitic activity compared with their respective bioactive ligands and moderate selectivity. To get insight into the anti-chagasic mechanism of action, the intracellular free radical production capacity of the gold compounds was assessed by ESR and fluorescence measurements. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and redox cycling processes were characterized. The potential oxidative stress mechanism against T. cruzi was confirmed.