新型 6-氨基-5-氰基-2-硫代嘧啶衍生物的设计、合成、分子建模和生物学评估，作为抗白血病和细胞凋亡诱导剂的有效抗癌剂。
Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers.
发表日期：2024 Dec
作者：
Naglaa M Ahmed, Mosaad S Mohamed, Samir M Awad, Rania H Abd El-Hameed, Neama A Abd El-Tawab, Mohamed S Gaballah, Ahmed M Said
来源：
J Enzym Inhib Med Ch
摘要：
在此，制备了一系列新型6-氨基-5-氰基-2-硫代嘧啶和缩合嘧啶类似物。美国国家癌症研究所（NCI；美国马里兰州）针对 60 种细胞系评估了所有合成化合物（1a-c、2a-c、3a-c、4a-r 和 5a-c）的体外抗癌活性。化合物 1c 显示出有希望的抗癌活性，并被选用于五剂量测试。结果表明，化合物 1c 对所测试的 9 个癌症亚组具有广谱抗癌活性，在 GI50 水平上选择性比范围为 0.7 至 39，对白血病具有高选择性。机理研究表明，化合物 1c 对 PI3Kδ 表现出与 Duvelisib 相当的活性（IC50 分别为 0.0034 和 0.0025μM），并将细胞周期阻滞在 S 期，并在 HL60 和白血病 SR 细胞中显示早期和晚期凋亡的显着增加。化合物1c处理的HL60细胞中的坏死百分比显着增加，从1.13％增加到3.41％，化合物1c处理的白血病SR细胞中的坏死百分比从1.51％增加到4.72％。此外，化合物 1c 通过激活 caspase 3、Bax、P53 并抑制 Bcl2 来引发细胞凋亡。此外，1c 显示出针对人正常肺成纤维细胞系（WI-38 细胞）的良好安全性。对 PI3K 中的 Duvelisib 和化合物 1c 进行了分子分析。最后，这些结果表明2-硫代嘧啶衍生物1c可能作为未来设计新型抗癌药物的模型。
Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 μM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future.