Tyrosine kinase inhibition effects of novel Pyrazolo[1,5-a]pyrimidines and Pyrido[2,3-d]pyrimidines ligand: Synthesis, biological screening and molecular modeling studies.

Autor: El Sayed MT; Deparment of Applied Organic Chemistry, National Research Centre, 12622 Dokki, Egypt., Hussein HAR; Department of Photochemistry, National Research Centre, 12622 Dokki, Egypt., Elebiary NM; Department of Green Chemistry, National Research Centre, 12622 Dokki, Egypt., Hassan GS; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt. Electronic address: ghadasameh@mans.edu.eg., Elmessery SM; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt., Elsheakh AR; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt., Nayel M; National Cancer Institute, Chemotherapeutic Agents Repository, Fisher BioServices, Germantown, MD 20874, USA., Abdel-Aziz HA; Deparment of Applied Organic Chemistry, National Research Centre, 12622 Dokki, Egypt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2018 Aug; Vol. 78, pp. 312-323. Date of Electronic Publication: 2018 Mar 26.
DOI: 10.1016/j.bioorg.2018.03.009
Abstrakt: Tyrosine kinases are one of the most critical mediators in the signaling path way. Late studies have proved the part of tyrosine kinases in the pathophysiology of cancer diseases. This current research paper has focused on investigating the novel Pyrazolo[1,5-a]pyrimidines and Pyrido[2,3-d]pyrimidines as a small molecules that can inhibit tyrosine kinase in cancer cells. NCI protocol was applied to test the antitumor activity of such compounds. Leukemia and renal cancer cell lines proved to be sensitive to some derivatives such as 6b-d, 9a and 11 with GI% values ranging from 30.4 to 41.3%. In addition, compound 11 proved to be the most active against MCF-7 with GI% 62.5. The synthesized compounds were also evaluated for their inhibitory effects against EGFR kinase enzyme. Compound 9b proved to be the most active one among the synthesized series with inhibition % value of 81.72 at 25 nM concentration and IC 50 8.4 nM which is very close to the reference drug Sorafenib. In vitro cytotoxicity test was also performed using the MCF-7 breast cell line. Computer modeling using the active site of tyrosine kinase as a template and the most active tyrosine kinase inhibitors were calculated. Docking studies of the synthesized compounds into the active site of EGFR kinase domain showed good agreement with the obtained biological results.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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