Chemistry Department, University of Minho, Campus de Gualtar, Braga, Portugal.
Life and Health Sciences Research Institute (ICVS), University of Minho, Campus de Gualtar, Braga, Portugal.
ChemMedChem. 2023 Jan 17;18(2):e202200519. doi: 10.1002/cmdc.202200519. Epub 2022 Nov 15.
An in silico study focused on known cancer-related target proteins, identified a selection of imidazo[4,5-b]pyrrolo[3,4-d]pyridines as potentially active. These compounds were prepared by a novel synthetic approach, designed and developed in-house, based on the reaction of 5-amino-4-cyanoformimidoyl imidazoles with N-substituted cyanoacetamides. The substituted imidazolylpyrrolones obtained, were cyclized intramolecularly to generate the intended imidazo[4,5-b]pyrrolo[3,4-d]pyridines in a process catalyzed by DBU. Treating the imidazolylpyrrolones with an excess of triethyl orthoformate and heating at 80 °C in the presence of acid catalysis led to imidazopyrrolodiazepines. These compounds were screened for their anticancer potential, using the renal cell carcinoma cell line model (A498 and 786-O cell lines). Two compounds exhibited IC values in the low micromolar range with a good selectivity index, when compared to non-neoplastic kidney cell line HK2 and the reference compounds rapamycin, cediranib and sunitinib.
一项针对已知癌症相关靶蛋白的计算机研究，鉴定出一些咪唑并[4,5-b]吡咯并[3,4-d]吡啶类化合物具有潜在的活性。这些化合物是通过一种新的合成方法制备的，该方法是基于 5-氨基-4-氰基甲亚氨基咪唑与 N-取代的氰基乙酰胺的反应，在内部设计和开发的。所得到的取代的咪唑基吡咯酮在 DBU 的催化作用下，通过分子内环化反应生成预期的咪唑并[4,5-b]吡咯并[3,4-d]吡啶类化合物。用过量的原甲酸三乙酯处理咪唑基吡咯酮，并在酸催化下于 80°C 加热，导致生成咪唑并吡咯并二氮杂卓。使用肾癌细胞系模型（A498 和 786-O 细胞系），对这些化合物的抗癌潜力进行了筛选。与非肿瘤性肾细胞系 HK2 和参考化合物雷帕霉素、西地尼布和舒尼替尼相比，两种化合物在低微摩尔范围内表现出 IC 值，具有良好的选择性指数。
