Barbosa Maria Cristina S, de Souza Barbosa Camila, de Oliveira Júlia T, Moreira Natália Chermont S, de Miranda Martins Natália Rezende, Alves Gomes Gabrielle K, Caldeira Camila A, Alves E Costa Marília Ladeira, Martins Guimarães Daniel Silqueira, Guimarães Luciana, Nascimento Clebio S, de Pilla Varotti Fernando, Ribeiro Viana Gustavo Henrique, Santos Fabio Vieira Dos
Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del Rei, Campus Centro-Oeste, Av. Sebastião Gonçalves Coelho, 400, Divinópolis, MG 35501-296, Brazil.
Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del Rei, Campus Centro-Oeste, Av. Sebastião Gonçalves Coelho, 400, Divinópolis, MG 35501-296, Brazil; LQTC: Laboratório de Química Teórica e Computacional, Departamento de Ciências Naturais (DCNAT), Universidade Federal de São João Del-Rei (UFSJ), Campus Dom Bosco, 36301-160, São João Del-Rei, MG, Brazil.
Mutat Res Genet Toxicol Environ Mutagen. 2018 Jan;825:31-39. doi: 10.1016/j.mrgentox.2017.11.006. Epub 2017 Nov 24.
Theonella sp is an important source of biologically-active 3-alkylpyridine alkaloids (3-APAs) that has shown a wide variety of promising biological effects. In the present work, two new 3-APAs analogues were synthesized based on molecular modeling studies to act as potential antimalarial agents. These theoneladin C analogues, containing the thiocyanate group in their chemical structures, were synthesized and evaluated against Plasmodium falciparum (IC values ranging from 2.3 to 5.5μM). The structural and energetic analysis demonstrated a high chemical affinity of the two analogues for their target, the heme group. However, despite the good antimalarial activity, the compounds exhibited high cytotoxicity and a lack of selectivity for human cell lines. These findings prompted us to evaluate the cytotoxicity of these compounds against human cancer cell lines. In order to better understand the mechanisms responsible for the toxicity, a variety of genotoxicity assays were performed in vitro. One of the compounds assayed presented an interesting selectivity and high toxicity to the human colon cancer cell line RKO-AS45-1. In addition, the results of the micronucleus assay, comet assay, Ames assay and annexin-V/propidium iodide staining showed that the synthetic alkaloids were able to induce chromosomal mis-segregation and trigger cell death by apoptosis. These results demonstrate that the compounds assessed herein may be promising prototypes of anticancer chemotherapeutic agents.
西奥奈拉属物种是具有生物活性的3-烷基吡啶生物碱（3-APA）的重要来源，已显示出多种有前景的生物学效应。在本研究中，基于分子模型研究合成了两种新的3-APA类似物，作为潜在的抗疟剂。这些含有硫氰酸酯基团化学结构的西奥奈拉丁C类似物被合成并针对恶性疟原虫进行了评估（IC值范围为2.3至5.5μM）。结构和能量分析表明这两种类似物对其靶标血红素基团具有高化学亲和力。然而，尽管具有良好的抗疟活性，但这些化合物对人细胞系表现出高细胞毒性且缺乏选择性。这些发现促使我们评估这些化合物对人癌细胞系的细胞毒性。为了更好地理解毒性的作用机制，在体外进行了多种遗传毒性试验。所检测的一种化合物对人结肠癌细胞系RKO-AS45-1呈现出有趣的选择性和高毒性。此外，微核试验、彗星试验、艾姆斯试验和膜联蛋白V/碘化丙啶染色的结果表明，合成生物碱能够诱导染色体错分并通过凋亡触发细胞死亡。这些结果表明，本文评估的化合物可能是有前景的抗癌化疗药物原型。
