Part II: New candidates of pyrazole-benzimidazole conjugates as checkpoint kinase 2 (Chk2) inhibitors.

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., Khairat SHM; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, 12622, 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., 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 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., 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., Ramdan R; Radiobiology Unit, Belgian Nuclear Research Center (SCK•CEN), Mol, Belgium; Department of Basic Medical Sciences, Physiology Group, Ghent University, Ghent, Belgium., 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] 2018 Jan 20; Vol. 144, pp. 859-873. Date of Electronic Publication: 2017 Dec 08.
DOI: 10.1016/j.ejmech.2017.12.023
Abstrakt: The development of checkpoint kinase 2 (Chk2) inhibitors for the treatment of cancer has been an ongoing and attractive objective in drug discovery. In this study, twenty-one feasible pyrazole-benzimidazole conjugates were synthesized to study their effect against Chk2 activity using Checkpoint Kinase Assay. The antitumor activity of these compounds was investigated using SRB assay. A potentiation effect of the synthesized Chk2 inhibitors was also investigated using the genotoxic anticancer drugs cisplatin and doxorubicin on breast carcinoma, (ER+) cell line (MCF-7). In vivo Chk2 and antitumor activities of 8d as a single-agent, and in combination with doxorubicin, were evaluated in breast cancer bearing animals induced by N-methylnitrosourea. The effect of 8d alone and in combination with doxorubicin was also studied on cell-cycle phases of MCF-7 cells using flow cytometry analysis. The results revealed their potencies as Chk2 inhibitors with IC 50 ranges from 9.95 to 65.07 nM. Generally the effect of cisplatin or doxorubicin was potentiated by the effect of most of the compounds that were studied. The in vivo results indicated that the combination of 8d and doxorubicin inhibited checkpoint kinase activity more than either doxorubicin or 8d alone. There was a positive correlation between checkpoint kinase inhibition and the improvement observed in histopathological features. Single dose treatment with doxorubicin or 8d produced S phase cell cycle arrest whereas their combination created cell cycle arrest at G2/M from 8% in case of doxorubicin to 51% in combination. Gold molecular modelling studies displayed a high correlation to the biological results.
(Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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