Part I: Design, synthesis and biological evaluation of novel pyrazole-benzimidazole conjugates as checkpoint kinase 2 (Chk2) inhibitors with studying their activities alone and in combination with genotoxic drugs.

Autor: Galal SA; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, 12622, Egypt. Electronic address: sh12galal@hotmail.com., Abdelsamie AS; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, 12622, Egypt., Shouman SA; Department of Cancer Biology, National Cancer Institute, Cairo University, Egypt., Attia YM; Department of Cancer Biology, National Cancer Institute, Cairo University, Egypt., Ali HI; Department of Pharmaceutical Sciences, Texas A&M University Irma Lerma Rangel College of Pharmacy Kingsville, TX 78363, United States; Department of Pharmaceutical Chemistry, College of Pharmacy, Helwan University, Cairo, Egypt., Tabll A; Department of Microbial Biotechnology, Division of Genetic Engineering & Biotechnology, National Research Centre, 12622, Cairo, Egypt., El-Shenawy R; Department of Microbial Biotechnology, Division of Genetic Engineering & Biotechnology, National Research Centre, 12622, Cairo, Egypt., El Abd YS; Department of Microbial Biotechnology, Division of Genetic Engineering & Biotechnology, National Research Centre, 12622, Cairo, Egypt., Ali MM; Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, 12622, Cairo, Egypt., Mahmoud AE; Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, 12622, Cairo, Egypt., Abdel-Halim AH; Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, 12622, Cairo, Egypt., Fyiad AA; Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, 12622, Cairo, Egypt., Girgis AS; Pesticide Chemistry Department, National Research Centre, 12622, Cairo, Egypt., El-Diwani HI; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, 12622, Egypt.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2017 Jul 07; Vol. 134, pp. 392-405. Date of Electronic Publication: 2017 Apr 14.
DOI: 10.1016/j.ejmech.2017.03.090
Abstrakt: Activated checkpoint kinase 2 (Chk2) is a tumor suppressor as one of the main enzymes that affect the cell cycle. 2-Biarylbenzimidazoles are potent selective class of Chk2 inhibitors; the structure-based design was applied to synthesize a new series of this class with replacing the lateral aryl group by substituted pyrazoles. Ten pyrazole-benzimidazole conjugates from the best fifty candidates according to docking programs have been subjected to chemical synthesis in this study. The activities of the conjugates 5-14 as checkpoint kinase inhibitors and as antitumor alone and in combination with genotoxic drugs were evaluated. The effect of compounds 7 and 12 on cell-cycle phases was analyzed by flow cytometry analysis. Antitumor activity of compounds 7 and 12 as single-agents and in combinations with doxorubicin was assessed in breast cancer bearing animals induced by MNU. The Results indicated that compounds 5-14 inhibited Chk2 activity with high potency (IC 50 52.8 nM-5.5 nM). The cytotoxicity of both cisplatin and doxorubicin were significantly potentiated by the most of the conjugates against MCF-7 cell lines. Compounds 7 and 12 and their combinations with doxorubicin induced the cell cycle arrest in MCF-7 cells. Moreover, compound 7 exhibited marked higher antitumor activity as a single agent in animals than it's combination with doxorubicin or doxorubicin alone. The combination of compound 12 with doxorubicin was greatly effective on animal than their single-dose treatment. In conclusion, pyrazole-benzimidazole conjugates are highly active Chk2 inhibitors that have anticancer activity and potentiate activity of genotoxic anticancer therapies and deserve further evaluations.
(Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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