Development and Assessment of 1,5–Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK–2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation
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Published:2023-09-08
Issue:18
Volume:28
Page:6521
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ISSN:1420-3049
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Container-title:Molecules
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language:en
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Short-container-title:Molecules
Author:
Abdelrahman Kamal S.1ORCID, Hassan Heba A.2, Abdel-Aziz Salah A.13, Marzouk Adel A.14, Shams Raef5ORCID, Osawa Keima6, Abdel-Aziz Mohamed2, Konno Hiroyuki6ORCID
Affiliation:
1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt 2. Department of Medicinal Chemistry Faculty of Pharmacy, Minia University, Minia 61519, Egypt 3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia 61768, Egypt 4. National Center for Natural Products Research, School of Pharmacy, University of Missippi, Oxford, MS 38677, USA 5. Emergent Bioengineering Materials Research Team, RIKEN Centre for Emergent Matter Science, RIKEN, Wako 351-0198, Saitama, Japan 6. Graduate School of Science and Engineering, Yamagata University, Yonezawa 992-8510, Yamagata, Japan
Abstract
New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a–j, 8a–j, 9a–c, and 10a–c. The oxime containing compounds 8a–j and 10a–c were more active as antiproliferative agents than their non-oxime congeners 7a–j and 9a–c. Compounds 8d, 8g, 8i, and 10c inhibited EGFR with IC50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d, 8g, 8i, and 10c exhibited binding free energies ranging from −12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from −9.16 to −12.00 kcal/mol at the JNK-2 binding site.
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
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