Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents

Molecules

Nabil Shurrab¹  Bassam Abu Thaher²  Said El-Kurdi²  Basem Qeshta²  Saeb Aliwaini³  Mariam Ghunaim³  Dieter Schollmeyer⁴  René Csuk⁵  Stefan Laufer⁶  Ihab Al-Masri⁷  Lars Kaiser⁸  Hans-Peter Deigner⁸ 

[1] Chemistry Department, Al Azhar University-Gaza, Gaza P.O. Box 1277, Palestine;Chemistry Department, Faculty of Science, Islamic University of Gaza, Gaza P.O. Box 108, Palestine;Department of Biology and Biotechnology, Islamic University of Gaza, Gaza P.O. Box 108, Palestine;Department of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, 55099 Mainz, Germany;Department of Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle, Germany;Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany;Faculty of Pharmacy, Al-Azhar University, Gaza P.O. Box 1277, Palestine;Institute of Precision Medicine, Faculty of Medical and Life Sciences, Furtwangen University (HFU), Jakob-Kienzle-Strasse 17, 78054 Villingen-Schwenningen, Germany;

关键词: pyrazolo[1,2,4]triazolopyrimidine;    EGF-receptor inhibitor;    breast cancer;    cervical cancer;    molecular docking;    crystal X-ray analysis;   

DOI  :  10.3390/molecules26134065

来源: DOAJ

【 摘 要 】

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

【 授权许可】

Unknown