在本研究中，根据 1,3,5-三嗪的药效特征，设计了新型取代的 1,3,5-三嗪候选物（4a-d、5a-j 和 6a-d）作为第二代小分子，作为 IDH1 和 IDH2 双重抑制剂。沃拉西尼和埃那西尼。用于白血病细胞系的化合物 6a 和 6b 显示出低至亚微摩尔的 GI50。此外，化合物4c、5f和6b描述了针对THP1和Kasumi白血病癌细胞的前沿抗肿瘤活性，其IC50值为（10和12）、（10.5和7）和（6.2和5.9）μg/mL，这是优异的分别为顺铂（25 和 28）μg/mL。有趣的是，化合物 4c、6b 和 6d 代表了最佳的双重 IDH1(R132H)/IDH2(R140Q) 抑制潜力，IC50 值为（0.72 和 1.22）、（0.12 和 0.93）和（0.50 和 1.28）μg/mL，分别与 vorasidenib（0.02 和 0.08）μg/mL 和enasidenib（0.33 和 1.80）μg/mL 相比。此外，最活跃的候选物 (6b) 对 HIF-1α、VEGF 和 SDH 具有非常有前景的抑制潜力，此外，还观察到 ROS 显着增加。此外，化合物6b诱导P53、BAX、Caspase 3、6、8和9蛋白分别上调3.70、1.99、2.06、1.73、1.75和1.85倍变化，以及BCL-2蛋白的下调与对照相比变化了 0.55 倍。此外，在携带实体艾氏癌肿瘤的雌性小鼠中评估了化合物6b作为抗肿瘤剂的体内行为。值得注意的是，化合物 6b 给药导致肿瘤重量和体积显着下降，同时生化、血液学和组织学参数也得到改善。版权所有 © 2024 Elsevier Inc. 保留所有权利。

In this study, novel substituted 1,3,5-triazine candidates (4a-d, 5a-j, and 6a-d) were designed as second-generation small molecules to act as dual IDH1 and IDH2 inhibitors according to the pharmacophoric features of both vorasidenib and enasidenib. Compounds 6a and 6b for leukemia cell lines showed from low to sub-micromolar GI50. Moreover, compounds 4c, 5f, and 6b described the frontier antitumor activity against THP1 and Kasumi Leukemia cancer cells with IC50 values of (10 and 12), (10.5 and 7), and (6.2 and 5.9) µg/mL, which were superior to those of cisplatin (25 and 28) µg/mL, respectively. Interestingly, compounds 4c, 6b, and 6d represented the best dual IDH1(R132H)/IDH2(R140Q) inhibitory potentials with IC50 values of (0.72 and 1.22), (0.12 and 0.93), and (0.50 and 1.28) µg/mL, respectively, compared to vorasidenib (0.02 and 0.08) µg/mL and enasidenib (0.33 and 1.80) µg/mL. Furthermore, the most active candidate (6b) has very promising inhibitory potentials towards HIF-1α, VEGF, and SDH, besides, a marked increase of ROS was observed as well. Besides, compound 6b induced the upregulation of P53, BAX, Caspases 3, 6, 8, and 9 proteins by 3.70, 1.99, 2.06, 1.73, 1.75, and 1.85-fold changes, respectively, and the downregulation for the BCL-2 protein by 0.55-fold change compared to the control. Besides, the in vivo behavior of compound 6b as an antitumor agent was evaluated in female mice bearing solid Ehrlich carcinoma tumors. Notably, compound 6b administration resulted in a prominent decrease in the weight and volume of the tumors, accompanied by improvements in biochemical, hematological, and histological parameters.Copyright © 2024 Elsevier Inc. All rights reserved.