Abstract

Abstract

New 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC50 values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFRWT). Compound 12b was the most potent member showing an IC50 value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFRT790M) (IC50 = 0.236 µM). Flow cytometric analyses revealed that compound 12b is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFRWT and EGFRT790M.

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Details

Title
Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M
Author
Gaber, Ahmed A 1 ; Sobhy, Mohamed 1 ; Turky, Abdallah 1 ; Hanan Gaber Abdulwahab 2 ; Al-Karmalawy, Ahmed A 3 ; Elhendawy, Mostafa A 4 ; Radwan, Mohamed M 5 ; Elkaeed, Eslam B 6 ; Ibrahim, Ibrahim M 7 ; Elzahabi, Heba S A 2 ; Eissa, Ibrahim H 8 

1  Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University , Cairo , Egypt 
2  Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University , Cairo , Egypt 
3  Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt , New Damietta , Egypt 
4  Department of Chemistry and Biochemistry, University of Mississippi , MS , USA, Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University , Damietta , Egypt 
5  National Center for Natural Products Research, University of Mississippi, University , MS , USA, Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University , Alexandria , Egypt 
6  Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University , Riyadh , Saudi Arabia 
7  Biophysics Department, Faculty of Science, Cairo University , Cairo , Egypt 
8  Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University , Cairo , Egypt 
Pages
2283-2303
Publication year
2022
Publication date
Dec 2022
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1080/14756366.2022.2112575
ProQuest document ID
2727916094
Copyright
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.