Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation
| Autor: | Stella Fountoulaki, Maria V Deligiorgi, Konstantinos Almpanakis, Sofia Sagredou, Dimitrios T Trafalis, Maria Voura, Panayiotis Dalezis, Vasiliki Sarli, Nikolaos Nikoleousakos |
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| Rok vydání: | 2021 |
| Předmět: |
lcsh:RS1-441
Pharmaceutical Science AKT2 Pharmacology anticancer Article lcsh:Pharmacy and materia medica 03 medical and health sciences inhibitor of Akt phosphorylation 0302 clinical medicine Thiadiazoles In vivo MTT assay Protein kinase B 030304 developmental biology 1 2 4-triazolo[3 4-b]-1 2 4-thiadiazole 0303 health sciences Chemistry ATP binding site In vitro HT-29 human colon tumor xenograft 030220 oncology & carcinogenesis Cancer cell Phosphorylation |
| Zdroj: | Pharmaceutics Volume 13 Issue 4 Pharmaceutics, Vol 13, Iss 493, p 493 (2021) |
| ISSN: | 1999-4923 |
| Popis: | 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-b]-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-b]-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-b]-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-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents. |
| Databáze: | OpenAIRE |
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