Cátedra de Química Inorgánica, Departamento Estrella Campos, Facultad de Química, Universidad de la República (UdelaR), Gral. Flores 2124, 11800 Montevideo, Uruguay.
Biol Trace Elem Res. 2013 Jun;153(1-3):371-81. doi: 10.1007/s12011-013-9653-4. Epub 2013 Apr 7.
In the search for new metal-based drugs against diseases produced by trypanosomatid parasites, four organoruthenium(II) compounds [Ru2(p-cymene)2(L)2]X2, where L are bioactive 5-nitrofuryl-containing thiosemicarbazones and X = Cl or PF6, had been previously obtained. These compounds had shown activity on Trypanosoma brucei, the etiological agent of African trypanosomiasis. Because of genomic similarities between trypanosomatides, these ruthenium compounds were evaluated, in the current work, on Trypanosoma cruzi, the parasite responsible of American trypanosomiasis (Chagas disease). Two of them showed significant in vitro growth inhibition activity against the infective trypomastigote form of T. cruzi (Dm28c clone, IC50 = 11.69 and 59.42 μM for [Ru2(p-cymene)2(L4)2]Cl2 and [Ru2(p-cymene)2(L1)2]Cl2, respectively, where HL4 = 5-nitrofuryl-N-phenylthiosemicarbazone and HL1 = 5-nitrofurylthiosemicarbazone), showing fairly good selectivities toward trypanosomes with respect to mammalian cells (J774 murine macrophages). Moreover, [Ru2(p-cymene)2(L2)2]Cl2, where HL2 = 5-nitrofuryl-N-methylthiosemicarbazone, was synthesized in order to evaluate the effect of improved solubility on biological behavior. This new chloride salt showed higher activity against T. cruzi than that of the previously synthesized hexafluorophosphate one (Dm28c clone, IC50 = 14.30 μM for the former and 231.3 μM for the latter). In addition, the mode of antitrypanosomal action of the organoruthenium compounds was investigated. The complexes were not only able to generate toxic free radicals through bioreduction but they also interacted with two further potential parasite targets: DNA and cruzipain, a cysteine protease which plays a fundamental role in the biological cycle of these parasites. The results suggest a "multi-target" mechanism of trypanosomicidal action for the obtained complexes.
在寻找针对由利什曼原虫寄生虫引起的疾病的新型金属基药物的过程中，先前已获得四种有机钌（II）化合物[Ru2（p-cymene）2（L）2]X2，其中 L 是具有生物活性的 5-硝基糠基含硫代半卡巴腙，X = Cl 或 PF6。这些化合物对引起非洲锥虫病的布氏锥虫（Trypanosoma brucei）表现出活性。由于利什曼原虫之间的基因组相似性，因此在当前的工作中，这些钌化合物在负责美洲锥虫病（恰加斯病）的寄生虫克氏锥虫（Trypanosoma cruzi）上进行了评估。其中两种化合物对感染性锥虫的鞭毛体形式的 T. cruzi（Dm28c 克隆，IC50 = 11.69 和 59.42 μM）表现出显著的体外生长抑制活性[Ru2（p-cymene）2（L4）2]Cl2 和 [Ru2（p-cymene）2（L1）2]Cl2，其中 HL4 = 5-硝基糠基-N-苯基硫代半卡巴腙和 HL1 = 5-硝基糠基硫代半卡巴腙），与哺乳动物细胞（J774 鼠巨噬细胞）相比，对锥虫具有相当好的选择性。此外，为了评估提高溶解度对生物学行为的影响，合成了[Ru2（p-cymene）2（L2）2]Cl2，其中 HL2 = 5-硝基糠基-N-甲基硫代半卡巴腙。该新氯化物盐对 T. cruzi 的活性高于先前合成的六氟磷酸盐盐（Dm28c 克隆，IC50 = 14.30 μM 对前者和 231.3 μM 对后者）。此外，还研究了有机钌化合物的抗锥虫作用方式。这些配合物不仅能够通过生物还原产生有毒自由基，而且还能够与另外两个潜在的寄生虫靶标相互作用：DNA 和 cruzipain，这是一种半胱氨酸蛋白酶，在这些寄生虫的生物学周期中起着至关重要的作用。结果表明，获得的复合物具有“多靶标”的杀锥虫作用机制。
