State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, 550014, China; School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, 550014, China.
Eur J Med Chem. 2023 Aug 5;256:115470. doi: 10.1016/j.ejmech.2023.115470. Epub 2023 May 8.
A series of new N-aryl-2-trifluoromethylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline by introducing a trifluoromethyl group into 2-position. The structures of the twenty-four newly synthesized compounds were confirmed by H NMR, C NMR and ESI-MS. The in vitro anti-cancer activity against chronic myeloid leukemia cells (K562), erythroleukemia cells (HEL), human prostate cancer cells (LNCaP), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, compounds 15d, 15f, 15h, and 15i showed the significantly (P < 0.01) stronger growth inhibitory activity on K562 than those of the positive controls of paclitaxel and colchicine, while compounds 15a, 15d, 15e, and 15h displayed significantly stronger growth inhibitory activity on HEL than those of the positive controls. However, all the target compounds exhibited weaker growth inhibition activity against K562 and HeLa than those of the positive controls. The selectivity ratio of compounds 15h, 15d, and 15i were significantly higher than those of other active compounds, indicating that these three compounds had the lower hepatotoxicity. Several compounds displayed strong inhibition against leukemia cells. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted cell cycle arrest of leukemia cells at G2/M phase and cell apoptosis, as well as inhibiting angiogenesis. In summary, our research provided that novel synthesized N-aryl-2-trifluoromethyl-quinazoline-4-amine active derivatives as the inhibitors of tubulin polymerization in leukemia cells, which might be a valuable lead compounds for anti-leukemia agents.
基于喹唑啉结构优化，通过在 2-位引入三氟甲基基团，设计并合成了一系列新型 N-芳基-2-三氟甲基喹唑啉-4-胺类似物。通过 1H NMR、13C NMR 和 ESI-MS 对新合成的 24 种化合物的结构进行了确认。评价了目标化合物对慢性髓系白血病细胞（K562）、红白血病细胞（HEL）、人前列腺癌细胞（LNCaP）和宫颈癌细胞（HeLa）的体外抗癌活性。其中，化合物 15d、15f、15h 和 15i 对 K562 的生长抑制活性明显（P<0.01）强于紫杉醇和秋水仙碱阳性对照物，而化合物 15a、15d、15e 和 15h 对 HEL 的生长抑制活性明显强于阳性对照物。然而，所有目标化合物对 K562 和 HeLa 的生长抑制活性均弱于阳性对照物。化合物 15h、15d 和 15i 的选择性比值明显高于其他活性化合物，表明这三种化合物的肝毒性较低。一些化合物对白血病细胞具有较强的抑制作用。它们通过靶向秋水仙碱结合位点抑制微管蛋白聚合，破坏细胞微管网络，促进白血病细胞 G2/M 期细胞周期阻滞和细胞凋亡，同时抑制血管生成。综上所述，我们的研究提供了新型合成的 N-芳基-2-三氟甲基-喹唑啉-4-胺活性衍生物作为白血病细胞微管蛋白聚合抑制剂，可能是抗白血病药物的有价值的先导化合物。
