Design, synthesis and molecular modeling study of certain 4-Methylbenzenesulfonamides with CDK2 inhibitory activity as anticancer and radio-sensitizing agents.

Autor: Ghorab MM; Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), PO box 29, Nasr City, Cairo, Egypt. Electronic address: mmsghorab@yahoo.com., Ragab FA; Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt., Heiba HI; Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), PO box 29, Nasr City, Cairo, Egypt., Elsayed MSA; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States., Ghorab WM; Department of Drug Radiation Research, National Centre for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), PO box 29, Nasr City, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2018 Oct; Vol. 80, pp. 276-287. Date of Electronic Publication: 2018 Jun 05.
DOI: 10.1016/j.bioorg.2018.06.010
Abstrakt: Two series of 2-aminopyridine derivatives 6-17 and tyrphostin AG17 analogs 18-22 bearing 4-methylbenzenesulfonamide moiety were designed and synthesized as anticancer compounds. The synthesized compounds were biologically evaluated for their cytotoxic activity against human breast cancer cell line MCF-7. From 2-aminopyridine and tyrphostin AG17 series, compounds 14, 16 and 20 showed the best activities with IC 50 values of 20.4, 18.3 and 26.3 µM, respectively compared to E7070 IC 50 36.3 µM. Further biological evaluation of 14, 16 and 20 against cyclin dependent kinase-2 (CDK2) revealed good inhibitory activity with IC 50 of 2.53, 1.79 and 2.92 µM, respectively compared to roscovitine IC 50 0.43 µM. Additionally, capability of γ-radiation to augment the cytotoxic activity of 14, 16 and 20 was studied and showed a dramatic increase in the cell killing effect at lower concentrations after irradiation. Docking was used to investigate the possible binding modes of compounds 14, 16 and 20 inside the active site of CDK2 enzyme.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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