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Differential lethal action of C17:2 and C17:0 anacardic acid derivatives in Trypanosoma cruzi - A mechanistic study.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-07-02 , DOI: 10.1016/j.bioorg.2020.104068
Eric Umehara 1 , Thais A Costa Silva 1 , Viviane M Mendes 2 , Rafael C Guadagnin 3 , Patricia Sartorelli 3 , Andre G Tempone 2 , João Henrique G Lago 1
Affiliation  

The n-hexane extract from leaves of Schinus terebinthifolius (Anacardiaceae) induced 100% of death of trypomastigote forms of T. cruzi at 300 μg/mL and was subjected to a bioactivity-guided fractionation to afford a C17:2 derivative of anacardic acid [6-(8′Z,11′Z)-heptadecadienyl-salicylic acid, 1]. Additionally, compound 1 was subjected to hydrogenation procedures to afford a C17:0 derivative (6-heptadecanyl-salicylic acid, 1a). Compounds 1 and 1a were effective in killing trypomastigote forms of T. cruzi with IC50 values of 8.3 and 9.0 μM, respectively, while a related compound, salicylic acid, was inactive. Furthermore, no cytotoxicity was observed for the highest tested concentration (CC50 > 200 µM) for all evaluated compounds. Due to the promising results, the mechanism of parasite death was investigated for compounds 1 and 1a using flow cytometry and spectrofluorimetry. The cell membrane permeability assay with SYTOX Green indicated that compound 1 significantly altered this parameter after 40 min of incubation, while compound 1a caused no alteration. Considering that the hydrogenation rendered a differential cellular target in parasites, additional assays were performed with 1a. Despite no permeabilization of the plasma membrane, compound 1a induced depolarization of the electric potential after two hours of incubation. The mitochondria of the parasite were also affected by compound 1a, with depolarization of the mitochondrial membrane potential, and reduction of reactive oxygen species (ROS) levels. The Ca2+ levels were not affected during the time of incubation. Considering that the mitochondrion is a single organelle in Trypanosoma cruzi for ATP generation, compounds affecting the bioenergetic system are of interest for drug discovery against Trypanosomatids.



中文翻译:

克鲁氏锥虫中C17:2和C17:0漆树酸衍生物的微分致死作用-机理研究。

所述Ñ从叶提取物正己烷肖乳香属terebinthifolius(漆树科)诱导的锥鞭毛体形式的死亡的100%锥虫在300μg/ mL和物进行生物活性引导分级,得到C17:2衍生物漆树酸的[ 6-(8' ž,11' ž)-heptadecadienyl水杨酸,1 ]。另外,将化合物1进行氢化步骤以提供C17:0衍生物(6-十七碳烯基-水杨酸,1a)。化合物11A在杀死锥鞭毛体形式的是有效的锥虫带IC 50值分别为8.3和9.0μM,而相关化合物水杨酸则没有活性。此外, 对于所有评估的化合物,最高测​​试浓度(CC 50 > 200 µM)均未观察到细胞毒性。由于有希望的结果使用流式细胞术和荧光光谱法研究了化合物11a的寄生虫死亡机理。用SYTOX Green进行的细胞膜通透性测定表明,孵育40分钟后,化合物1显着改变了该参数,而化合物1a没有引起改变。考虑到氢化作用使寄生虫中的细胞靶标差异化,用1a。尽管质膜未透化,但在孵育2小时后,化合物1a引起电势的去极化。化合物1a也会影响寄生虫的线粒体,使其线粒体膜电位去极化,并降低活性氧(ROS)水平。在孵育期间,Ca 2+的水平不受影响。考虑到线粒体是克鲁斯锥虫中用于产生ATP的单个细胞器,因此影响生物能系统的化合物对于针对锥虫的药物发现很重要。

更新日期:2020-07-09
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