Gonçalves Ana C R, Carneiro Zumira A, Oliveira Carolina G, Danuello Amanda, Guerra Wendell, Oliveira Ronaldo J, Ferreira Francis B, Veloso-Silva Laudimir L W, Batista Fernanda A H, Borges Júlio C, de Albuquerque Sérgio, Deflon Victor M, Maia Pedro I S
Núcleo de Desenvolvimento de Compostos Bioativos (NDCBio), Universidade Federal do Triângulo Mineiro, Av. Dr. Randolfo Borges 1400, 38025-440, Uberaba, MG, Brazil.
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, FCFRP-USP, Universidade de São Paulo, Avenida do Café s/n, 14040-903, Ribeirão Preto, SP, Brazil.
Eur J Med Chem. 2017 Dec 1;141:615-631. doi: 10.1016/j.ejmech.2017.10.013. Epub 2017 Oct 12.
New complexes of composition [MX(HL1)] (M = Pt, Pd, X = Cl or I) and [MX(L1)] (M = Au, X = Cl; M = Pt, Pd, X = PPh) have been synthesized using a potentially tridentate thiosemicarbazone (HL1) containing an additional oxime binding site. Among other analytical methods, all the seven complexes have been structurally characterized by single crystal X-ray diffractometry. Interesting structural features such as the influence of the halide ligands on hydrogen bonds and the formation of supramolecular structures for the phosphine derivatives are discussed. The in vitro trypanocidal activity of the free ligand HL1 and its derivatives against both extracellular trypomastigote and intracellular amastigote (IC) forms of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity was assessed on LLC-MK2 cell line. The results showed that complexation of the thiosemicarbazone ligand HL1 to Pt, Pd and Au metal centers enhances the in vitro trypanocidal activity and that the cytotoxicity is dependent on both the metal center and coligands. Within the studied series, the Au complex showed the greatest potential, being not the most active but the most selective compound with a similar selectivity index to that of the standard drug benznidazole. In order to get a preliminary insight into the mechanism of action of these compounds, in vitro experiments of fluorescence quenching and enzymatic activity were performed using the Au complex and Trypanosoma cruzi Old Yellow Enzyme (TcOYE) which indicated that the gold derivative was capable of abstracting the hydride from the prosthetic FMN group of the enzyme. Additionally, molecular docking studies followed by semiempirical simulations showed that the [AuCl(L1)] binds to the binary complex TcOYE/FMN, almost parallel to the FMN prosthetic group, in a close distance that an electron/proton transfer might occur among them.
合成了组成式为[MX(HL1)]（M = Pt、Pd，X = Cl或I）和[MX(L1)]（M = Au，X = Cl；M = Pt、Pd，X = PPh）的新型配合物，所用的是一种含有额外肟结合位点的潜在三齿硫代半卡巴腙（HL1）。在其他分析方法中，所有这七种配合物都通过单晶X射线衍射法进行了结构表征。讨论了一些有趣的结构特征，如卤化物配体对氢键的影响以及膦衍生物超分子结构的形成。研究了游离配体HL1及其衍生物对克氏锥虫（图拉温Lac-Z株）细胞外锥鞭毛体和细胞内无鞭毛体（IC）形式的体外杀锥虫活性，并在LLC-MK2细胞系上评估了细胞毒性。结果表明，硫代半卡巴腙配体HL1与Pt、Pd和Au金属中心形成配合物可增强体外杀锥虫活性，且细胞毒性取决于金属中心和共配体。在所研究的系列中，金配合物显示出最大的潜力，它不是活性最高的化合物，但却是选择性最高的化合物，其选择性指数与标准药物苯硝唑相似。为了初步了解这些化合物的作用机制，使用金配合物和克氏锥虫老黄色酶（TcOYE）进行了体外荧光猝灭和酶活性实验，结果表明金衍生物能够从该酶的辅基FMN基团中提取氢化物。此外，分子对接研究和半经验模拟表明，[AuCl(L1)]与二元复合物TcOYE/FMN结合，几乎与FMN辅基平行，距离很近，可能会在它们之间发生电子/质子转移。
