Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano 49, 80131 Napoli, Italy.
J Med Chem. 2013 Sep 12;56(17):6666-80. doi: 10.1021/jm400947b. Epub 2013 Aug 19.
The novel tetrasubstituted pyrrole derivatives 8g, 8h, and 8i showed selective cytotoxicity against M14 melanoma cells at low micromolar concentration. Structure-activity relationships (SARs) indicated the presence of three aromatic substituents on the pyrrole core as necessary for biological activity. Computational studies strongly suggest that the peculiar 3D orientation of these substituents is able to reproduce the hydrophobic side chains in LxxLL-like protein recognition motifs. Biological results showed altered p53 expression and nuclear translocation in cells sensitive to the compounds, suggesting p53 involvement in their anticancer mechanism of action. Unfortunately, because of poor solubility of the active analogues, it was not possible to perform further investigation by NMR techniques. Pharmacophore models were generated and used to perform 3D searches in molecular databases. Results indicated that two compounds share the same pharmacological profile and the same pharmacophoric features with our new derivatives, and one of them inhibited MDM2-MDM4 heterodimer formation.
新型四取代吡咯衍生物 8g、8h 和 8i 在低微摩尔浓度下对 M14 黑色素瘤细胞表现出选择性细胞毒性。构效关系（SAR）表明，吡咯核心上存在三个芳香取代基对于生物活性是必要的。计算研究强烈表明，这些取代基的特殊 3D 取向能够在 LxxLL 样蛋白识别基序中重现疏水性侧链。生物学结果表明，在对化合物敏感的细胞中，p53 表达和核转位发生改变，提示 p53 参与其抗癌作用机制。不幸的是，由于活性类似物的溶解度较差，无法通过 NMR 技术进一步进行研究。生成了药效团模型，并用于在分子数据库中进行 3D 搜索。结果表明，两种化合物具有相同的药理学特征和与我们的新衍生物相同的药效特征，其中一种化合物抑制了 MDM2-MDM4 异二聚体的形成。
