Part III: Novel checkpoint kinase 2 (Chk2) inhibitors; design, synthesis and biological evaluation of pyrimidine-benzimidazole conjugates.

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., Khattab M; 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., Ramadan R; Radiobiology Unit, Belgian Nuclear Research Center (SCK•CEN), Mol, Belgium; Department of Basic Medical Sciences, Physiology Group, Ghent University, Ghent, Belgium., Kandil OM; Department of Animal Reproduction & Artificial Insemination, Division, of Veterinary Research, National Research Centre, Cairo, 12622, Egypt., Kandil OM; Department of Parasitology, Animal Disease, Division, of Veterinary, National Research Centre, Cairo, 12622, Egypt., Tabll A; 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., El-Shenawy R; Department of Microbial Biotechnology, Division of Genetic Engineering & Biotechnology, National Research Centre, 12622, Cairo, Egypt., Attia YM; Department of Cancer Biology, National Cancer Institute, Cairo University, Egypt., El-Rashedy AA; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, 12622, 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] 2018 Feb 25; Vol. 146, pp. 687-708. Date of Electronic Publication: 2018 Feb 02.
DOI: 10.1016/j.ejmech.2018.01.072
Abstrakt: Recently a dramatic development of the cancer drug discovery has been shown in the field of targeted cancer therapy. Checkpoint kinase 2 (Chk2) inhibitors offer a promising approach to enhance the effectiveness of cancer chemotherapy. Accordingly, in this study many pyrimidine-benzimidazole conjugates were designed and twelve feasible derivatives were selected to be synthesized to investigate their activity against Chk2 and subjected to study their antitumor activity alone and in combination with the genotoxic anticancer drugs cisplatin and doxorubicin on breast carcinoma, (ER+) cell line (MCF-7). The results indicated that the studied compounds inhibited Chk2 activity with high potency (IC 50  = 5.56 nM - 46.20 nM). The studied candidates exhibited remarkable antitumor activity against MCF-7 (IG 50  = 6.6  μM - 24.9 μM). Compounds 10a-c, 14 and 15 significantly potentiated the activity of the studied genotoxic drugs, whereas, compounds 9b and 20-23 antagonized their activity. Moreover, the combination of compound 10b with cisplatin revealed the best apoptotic effect as well as combination of compound 10b with doxorubicin led to complete arrest of the cell cycle at S phase where more than 40% of cells are in the S phase with no cells at G2/M. Structure-activity relationship was discussed on the basis of molecular modeling study using Molecular modeling Environment program (MOE).
(Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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