PDF(Pubmed)
Abstract：
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.
摘要：
在这里，制备了一系列新的6-氨基-5-氰基-2-硫代嘧啶和缩合嘧啶类似物。所有合成的化合物（1a-c，2a-c,3a-c,4a-r和5a-c）由美国国家癌症研究所（NCI；MD，美国）针对60个细胞系。化合物Ic显示有希望的抗癌活性,并被选择用于五剂量测试。结果表明,化合物1c具有针对所测试的9个癌性子组的广谱抗癌活性,在GI50水平上的选择性比为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的活性与Duvelisib相当（IC50=0.0034和0.0025μM，分别）并将细胞周期阻滞在S期，并在HL60和白血病SR细胞的早期和晚期凋亡显着增加。在化合物1c处理的HL60细胞中,坏死百分比显示从1.13%至3.41%以及在化合物1c处理的白血病SR细胞中从1.51%至4.72%的显著增加。此外，化合物1c通过激活caspase3，Bax，P53和抑制Bcl2。此外，图1c显示针对人正常肺成纤维细胞系(WI-38细胞)的良好安全性。在PI3K中进行Duvelisib和化合物1c的分子分析。最后,这些结果表明，2-硫代嘧啶衍生物1c可能成为未来设计新型抗癌药物的模型。
