Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, C.P. 09340, Iztapalapa, Mexico City, Mexico.
Departamento de Polímeros, Instituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria, Coyoacán, Mexico City C.P. 04510, Mexico.
Molecules. 2019 Jul 22;24(14):2648. doi: 10.3390/molecules24142648.
A series of 12 polysubstituted pyrrolo[3,4-]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi-3CR/ Diels-Alder/-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcinoma SiHa, HeLa, and CaSki cell line cultures. Three compounds of the series exhibited significative cytotoxicity against the three cell lines, with HeLa being the most sensitive one. Then, based on these results, in silico studies by docking techniques were performed using Paclitaxel as a reference and αβ-tubulin as the selected biological target. Worth highlighting is that strong hydrophobic interactions were observed between the three active molecules and the reference drug Paclitaxel, to the αβ-tubulin. In consequence, it was determined that hydrophobic-aromatic moieties of bioactive compounds and Paclitaxel play a key role in making stronger interactions to the ligand-target complex. A quantitative structure activity relationship (QSAR) study revealed that the six membered rings are the most significant molecular frameworks, being present in all proposed models for the in vitro-studied cell lines. Finally, also from the docking interpretation, a ligand-based pharmacophore model is proposed in order to find further potential polyheterocyclic candidates to bind stronger to the αβ-tubulin.
通过一锅级联过程（Ugi-3CR/Diels-Alder/-酰化/脱羧/脱水）合成了一系列 12 个多取代的吡咯并[3,4-]吡啶-5-酮，并在体外用人宫颈癌细胞系 SiHa、Hela 和 CaSki 细胞培养物进行了研究。该系列中的三种化合物对三种细胞系表现出显著的细胞毒性，其中 Hela 最为敏感。然后，基于这些结果，使用紫杉醇作为参考物，使用对接技术进行了计算机模拟研究，并选择了αβ-微管蛋白作为生物靶标。值得强调的是，在αβ-微管蛋白中，三种活性分子与参考药物紫杉醇之间观察到了强烈的疏水相互作用。因此，可以确定生物活性化合物和紫杉醇的疏水性-芳环部分在与配体-靶标复合物形成更强的相互作用中起着关键作用。定量构效关系（QSAR）研究表明，六元环是最重要的分子框架，存在于所有为体外研究的细胞系提出的模型中。最后，也从对接解释中，提出了基于配体的药效团模型，以便找到进一步的潜在多杂环候选物，以更强的亲和力与αβ-微管蛋白结合。
