Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation.

Autor: Soltan OM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt., Abdel-Aziz SA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, 61111 Minia, Egypt., Sh Shaykoon M; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt., Osawa K; Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Jonan 4-3-16, Yonezawa, Yamagata 992-8510, Japan., Narumi A; Department of Organic Materials Science, Graduate School of Organic Materials Science, Yamagata University, Jonan 4-3-16, Yonezawa, Yamagata 992-8510, Japan., Abdel-Aziz M; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt., Shoman ME; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt., Konno H; Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Jonan 4-3-16, Yonezawa, Yamagata 992-8510, Japan. Electronic address: konno@yz.yamagata-u.ac.jp.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Apr 01; Vol. 102, pp. 129673. Date of Electronic Publication: 2024 Feb 24.
DOI: 10.1016/j.bmcl.2024.129673
Abstrakt: The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC 50 ) values of 2.7-63 μM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC 50 of 2.0 and 0.9 μM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC 50  = 1.7 μM). Notably, 6c inhibited both kinases, with IC 50 values of 2.7 and 3.0 μM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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