da Silva Gustavo H O, Dos Santos Kevin F, Barcellos Aline F, de Sousa Raquel M Ferreira, Tempone Andre G, Lago João Henrique G, Caseli Luciano
Departamento de Química, Universidade Federal de São Paulo, Diadema, SP, Brazil.
Universidade Federal do ABC, Santo André, SP, Brazil.
Bioorg Chem. 2024 Dec;153:107941. doi: 10.1016/j.bioorg.2024.107941. Epub 2024 Nov 4.
A natural product isolated from Brazilian plant species Baccharis retusa (Asteraceae), 15β-senecioyloxi-ent-kaurenoic acid (1), demonstrated activity against trypomastigotes of the parasite Trypanosoma cruzi but it was inactive against intracellular forms. In the present work, compound 1a, a methyl ester derivative of 1, exhibited activity against intracellular amastigotes (EC = 11.8 μM), similar to that determined by the standard drug benznidazol (EC = 16.2 μM) and no toxicity against NCTC cells (CC > 200 μM). Based on this selectivity, compound 1a was incorporated into Langmuir monolayers of three lipids, DPPC, DPPE, and DPPS, to characterize the interaction of the compound with each lipid as model for cell membranes. For that, we used tensiometry, surface potential measurements, and infrared spectroscopy. Our results showed that incorporating the drug into DPPC monolayers significantly altered the physicochemical properties, resulting in more condensed monolayers. In contrast, the incorporation of the drug into DPPE and DPPS monolayers led to their expansion. The effects on DPPC were more pronounced than on the other lipids, inducing a viscoelastic monolayer with lower alignment of the alkyl chains, as observed through surface potential measurements and infrared spectroscopy. These changes indicate a more cohesive DPPC monolayer upon drug incorporation, forming domains in a strip shape. We believe these results contribute to understanding the interaction between 1a and lipid interfaces, especially those involved in biological interactions with amastigotes of parasite T. cruzi.
从巴西植物物种白花鬼针草（菊科）中分离出的一种天然产物15β-千里光酰氧基-对映-贝壳杉烯酸（1），对克氏锥虫的锥鞭毛体具有活性，但对细胞内形式无活性。在本研究中，化合物1a是1的甲酯衍生物，对细胞内无鞭毛体具有活性（EC = 11.8 μM），与标准药物苯硝唑测定的活性相似（EC = 16.2 μM），且对NCTC细胞无毒性（CC > 200 μM）。基于这种选择性，将化合物1a掺入三种脂质DPPC、DPPE和DPPS的朗缪尔单分子层中，以表征该化合物与每种脂质作为细胞膜模型的相互作用。为此，我们使用了张力测定法、表面电位测量法和红外光谱法。我们的结果表明，将药物掺入DPPC单分子层中会显著改变其物理化学性质，导致单分子层更加致密。相比之下，将药物掺入DPPE和DPPS单分子层中会导致它们膨胀。对DPPC的影响比对其他脂质更明显，通过表面电位测量和红外光谱观察到，诱导形成了烷基链排列较低的粘弹性单分子层。这些变化表明药物掺入后DPPC单分子层的内聚力更强，形成了带状结构域。我们相信这些结果有助于理解1a与脂质界面之间的相互作用，特别是那些与克氏锥虫无鞭毛体生物相互作用相关的界面。
