Nasr Tamer, Bondock Samir, Youns Mahmoud, Fayad Walid, Zaghary Wafaa
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Egypt.
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt; Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia.
Eur J Med Chem. 2017 Dec 1;141:603-614. doi: 10.1016/j.ejmech.2017.10.016. Epub 2017 Oct 10.
Design and synthesis of new anticancer scaffolds; pyrazolo[3,4-d][1,2,3]triazine derivatives, is a promising solution to overcome drug resistance problem. A series of (E)-2-cyano-N-(aryl)-3-methylthio-3-(substituted-amino)acrylamides 3a-e was synthesized and transformed to the 3-aminopyrazole derivatives 4a-e which were then transformed to the target pyrazolotriazinones 6a-e. All compounds were evaluated for their anticancer activity against three different cancer cell lines namely Huh-7, Panc-1 and CCRF. Compounds 3a, 3c, 6a and 6c showed excellent anticancer activity against Huh-7 cell line (IC: 4.93-8.84 μM vs doxorubicin 5.43 μM). Similarly, compounds 6a and 6d showed excellent activities against Panc-1 cells (IC: 9.91 μM and 4.93 μM vs doxorubicin 6.90 μM). Caspase-Glo 3/7 assay was done and the results revealed that the pro-apoptotic activity of the target compounds could be due to the stimulation of caspases 3/7. Microarray experiment for Huh-7 cells treated with 6c was performed to search for other molecular changes. SLC26A3, UGT1A1, UGT2B15, UGT2B7, DNASE1, MUCDH1 and UGT2B17 were among the up-regulated genes, while, GIP3, TAGL, THBS1, IFI27, FSCN1 and SOCS2 were among the most extensively down-regulated genes. These genes belong to apoptosis, metabolism, cell cycle, tumor growth and suppressor genes. Finally, pyrazolo[3,4-d][1,2,3]triazine derivatives could be potent anticancer drugs in the future.
新型抗癌骨架的设计与合成；吡唑并[3,4-d][1,2,3]三嗪衍生物是克服耐药性问题的一个有前景的解决方案。合成了一系列(E)-2-氰基-N-(芳基)-3-甲硫基-3-(取代氨基)丙烯酰胺3a-e，并将其转化为3-氨基吡唑衍生物4a-e，然后再转化为目标吡唑并三嗪酮6a-e。评估了所有化合物对三种不同癌细胞系即Huh-7、Panc-1和CCRF的抗癌活性。化合物3a、3c、6a和6c对Huh-7细胞系显示出优异的抗癌活性(IC：4.93 - 8.84 μM，而阿霉素为5.43 μM)。同样，化合物6a和6d对Panc-1细胞显示出优异的活性(IC：9.91 μM和4.93 μM，而阿霉素为6.90 μM)。进行了Caspase-Glo 3/7检测，结果表明目标化合物的促凋亡活性可能归因于对半胱天冬酶3/7的刺激。对用6c处理的Huh-7细胞进行了微阵列实验，以寻找其他分子变化。SLC26A3、UGT1A1、UGT2B15、UGT2B7、DNASE1、MUCDH1和UGT2B17是上调基因，而GIP3、TAGL、THBS1、IFI27、FSCN1和SOCS2是下调最广泛的基因。这些基因属于凋亡、代谢、细胞周期、肿瘤生长和抑制基因。最后，吡唑并[3,4-d][1,2,3]三嗪衍生物未来可能成为有效的抗癌药物。
