Trafalis Dimitrios T, Sagredou Sofia, Dalezis Panayiotis, Voura Maria, Fountoulaki Stella, Nikoleousakos Nikolaos, Almpanakis Konstantinos, Deligiorgi Maria V, Sarli Vasiliki
Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece.
Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 541 24 Thessaloniki, Greece.
Pharmaceutics. 2021 Apr 5;13(4):493. doi: 10.3390/pharmaceutics13040493.
The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time- and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents.
1,2,4-三唑与1,3,4-噻二唑环的融合产生了一类具有广泛药理特性的杂环化合物。合成了一系列1,2,4-三唑并[3,4-]-1,2,4-噻二唑，并测试了其酶抑制潜力和抗癌活性。结果表明，1,2,4-三唑并[3,4-]-1,2,4-噻二唑在体外对一组癌细胞显示出强大的抗癌特性，在CB17重度联合免疫缺陷（SCID）小鼠的HT-29人结肠肿瘤异种移植模型中具有体内疗效。初步机制研究表明，KA25和KA39对Akt Ser-473磷酸化表现出时间和浓度依赖性抑制。分子建模实验表明，1,2,4-三唑并[3,4-]-1,2,4-噻二唑与Akt1和Akt2中的ATP结合位点结合良好。低急性毒性以及体外和体内抗癌活性使三唑并[3,4-]噻二唑KA25、KA26和KA39成为有前景的癌症治疗药物。
