Laboratório de Sintese de Farmacos, Instituto de Tecnologia em Farmacos-Farmanguinhos, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro 21041-250, RJ, Brazil.
Programa de Pós-graduação em Farmacologia e Química Medicinal do Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Bloco J, Ilha do Fundão, Rio de Janeiro 21941-902, RJ, Brazil.
Molecules. 2022 Jan 24;27(3):750. doi: 10.3390/molecules27030750.
Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (), the 5-chloro-3,3-difluorinated compound () and the 5-bromo-3,3-difluorinated compound () showed IC values of 7.2, 6.4, and 7.3 μM, respectively, and were all more potent than imatinib (IC of 65.4 μM). In K562 cells, the 3,3-difluoro-5-methylated compound () decreased cell viability to 57.5% and, at 10 µM, showed an IC value of 35.8 μM (imatinib, IC = 0.08 μM). The results suggest that , , and can be used as prototypes for the development of more potent and selective derivatives against lung cancer.
酪氨酸激酶酶是治疗某些人类肿瘤（如肺癌和慢性髓性白血病）的主要分子靶标之一。酶结构域的突变会导致耐药性，而能够规避这些突变的新型抑制剂则备受期待。本工作的目的是合成和评估十种新的类似物的抗增殖能力，这些类似物含有色氨酸和苯氨基嘧啶吡啶（PAPP）骨架，这是伊马替尼的主要药效团。1,2,3-三唑核心通过点击化学反应被用作衍生物的间隔物，产率良好。所有类似物均针对 A549 和 K562 细胞（肺癌和慢性髓性白血病（CML）细胞系）进行了测试。在 A549 细胞中，3,3-二氟化合物（）、5-氯-3,3-二氟化合物（）和 5-溴-3,3-二氟化合物（）的 IC 值分别为 7.2、6.4 和 7.3 μM，均比伊马替尼（IC = 65.4 μM）更有效。在 K562 细胞中，3,3-二氟-5-甲基化合物（）使细胞活力降低至 57.5%，在 10 μM 时，IC 值为 35.8 μM（伊马替尼，IC = 0.08 μM）。结果表明，、和可以作为开发针对肺癌的更有效和选择性衍生物的原型。
