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

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 13; p. 4065
• Main Authors: Aliwaini, Saeb, Abu Thaher, Bassam, Al-Masri, Ihab, Shurrab, Nabil, El-Kurdi, Said, Schollmeyer, Dieter, Qeshta, Basem, Ghunaim, Mariam, Csuk, René, Laufer, Stefan, Kaiser, Lars, Deigner, Hans-Peter
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 02.07.2021; MDPI
• Subjects: Adenosine triphosphate; AKT protein; Apoptosis; Binding sites; Biological activity; Breast cancer; Cancer therapies; Cell cycle; Cell growth; Cervical cancer; Cervix; Competition; Crystal structure; crystal X-ray analysis; Cytotoxicity; EGF-receptor inhibitor; Epidermal growth factor; Epidermal growth factor receptors; Extracellular signal-regulated kinase; Growth factors; Kinases; Ligands; Lung cancer; molecular docking; NMR; Nuclear magnetic resonance; pyrazolo[1,2,4]triazolopyrimidine; Single crystals; Tumor cell lines; X ray analysis
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26134065

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.