Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents
Three novel pyrazolo-[4,3-<i>e</i>][1,2,4]triazolopyrimidine derivatives (<b>1</b>, <b>2</b>, and <b>3</b>) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity...
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| Format: | Article |
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MDPI AG
2021-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/13/4065 |
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| author | Saeb Aliwaini Bassam Abu Thaher Ihab Al-Masri Nabil Shurrab Said El-Kurdi Dieter Schollmeyer Basem Qeshta Mariam Ghunaim René Csuk Stefan Laufer Lars Kaiser Hans-Peter Deigner |
| author_facet | Saeb Aliwaini Bassam Abu Thaher Ihab Al-Masri Nabil Shurrab Said El-Kurdi Dieter Schollmeyer Basem Qeshta Mariam Ghunaim René Csuk Stefan Laufer Lars Kaiser Hans-Peter Deigner |
| author_sort | Saeb Aliwaini |
| collection | DOAJ |
| description | Three novel pyrazolo-[4,3-<i>e</i>][1,2,4]triazolopyrimidine derivatives (<b>1</b>, <b>2</b>, and <b>3</b>) 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 <b>1</b> 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 <b>1</b> 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 <b>1</b> at the ATP binding site of EGFR. Furthermore, the crystal structure of compound <b>3</b> (7-(4-bromophenyl)-9-(pyridin-4-yl)-7<i>H</i>-pyrazolo[4,3-<i>e</i>][1,2,4]triazolo[1,5-<i>c</i>]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. |
| first_indexed | 2024-03-10T09:51:02Z |
| format | Article |
| id | doaj.art-a77c83942f3d4f95a43c4dc95beddc7d |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T09:51:02Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a77c83942f3d4f95a43c4dc95beddc7d2023-11-22T02:47:34ZengMDPI AGMolecules1420-30492021-07-012613406510.3390/molecules26134065Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer AgentsSaeb Aliwaini0Bassam Abu Thaher1Ihab Al-Masri2Nabil Shurrab3Said El-Kurdi4Dieter Schollmeyer5Basem Qeshta6Mariam Ghunaim7René Csuk8Stefan Laufer9Lars Kaiser10Hans-Peter Deigner11Department of Biology and Biotechnology, Islamic University of Gaza, Gaza P.O. Box 108, PalestineChemistry Department, Faculty of Science, Islamic University of Gaza, Gaza P.O. Box 108, PalestineFaculty of Pharmacy, Al-Azhar University, Gaza P.O. Box 1277, PalestineChemistry Department, Al Azhar University-Gaza, Gaza P.O. Box 1277, PalestineChemistry Department, Faculty of Science, Islamic University of Gaza, Gaza P.O. Box 108, PalestineDepartment of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, 55099 Mainz, GermanyChemistry Department, Faculty of Science, Islamic University of Gaza, Gaza P.O. Box 108, PalestineDepartment of Biology and Biotechnology, Islamic University of Gaza, Gaza P.O. Box 108, PalestineDepartment of Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle, GermanyDepartment of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, GermanyInstitute of Precision Medicine, Faculty of Medical and Life Sciences, Furtwangen University (HFU), Jakob-Kienzle-Strasse 17, 78054 Villingen-Schwenningen, GermanyInstitute of Precision Medicine, Faculty of Medical and Life Sciences, Furtwangen University (HFU), Jakob-Kienzle-Strasse 17, 78054 Villingen-Schwenningen, GermanyThree novel pyrazolo-[4,3-<i>e</i>][1,2,4]triazolopyrimidine derivatives (<b>1</b>, <b>2</b>, and <b>3</b>) 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 <b>1</b> 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 <b>1</b> 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 <b>1</b> at the ATP binding site of EGFR. Furthermore, the crystal structure of compound <b>3</b> (7-(4-bromophenyl)-9-(pyridin-4-yl)-7<i>H</i>-pyrazolo[4,3-<i>e</i>][1,2,4]triazolo[1,5-<i>c</i>]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.https://www.mdpi.com/1420-3049/26/13/4065pyrazolo[1,2,4]triazolopyrimidineEGF-receptor inhibitorbreast cancercervical cancermolecular dockingcrystal X-ray analysis |
| spellingShingle | Saeb Aliwaini Bassam Abu Thaher Ihab Al-Masri Nabil Shurrab Said El-Kurdi Dieter Schollmeyer Basem Qeshta Mariam Ghunaim René Csuk Stefan Laufer Lars Kaiser Hans-Peter Deigner Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents Molecules pyrazolo[1,2,4]triazolopyrimidine EGF-receptor inhibitor breast cancer cervical cancer molecular docking crystal X-ray analysis |
| title | Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents |
| title_full | Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents |
| title_fullStr | Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents |
| title_full_unstemmed | Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents |
| title_short | Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents |
| title_sort | design synthesis and biological evaluation of novel pyrazolo 1 2 4 triazolopyrimidine derivatives as potential anticancer agents |
| topic | pyrazolo[1,2,4]triazolopyrimidine EGF-receptor inhibitor breast cancer cervical cancer molecular docking crystal X-ray analysis |
| url | https://www.mdpi.com/1420-3049/26/13/4065 |
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