Design and synthesis of new anticancer pyrimidines with multiple-kinase inhibitory effect

• Published in: Bioorganic & medicinal chemistry 2010-06, Vol.18 (11), p.3860-3874
• Main Authors: El-Deeb, Ibrahim Mustafa, Lee, So Ha
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Benzamides; Biological and medical sciences; Cell Line, Tumor; Drug Design; General aspects; Humans; Imatinib Mesylate; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Molecular modeling; Multiple-kinase; Pharmacology. Drug treatments; Piperazines; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-abl - metabolism; Pyrimidine; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.037

A new series of N-substituted-2-aminopyrimidines has been designed, synthesized, and tested over a panel of 60 cancer cell lines. Compound 30 has showed multiple inhibitions over a number of oncogenic kinases. A molecular modeling study was made by docking of the most active compound 30 into the kinase domain of ABL1 to investigate its possible binding interactions. A new series of N-substituted-2-aminopyrimidines based on the ‘4-(pyridin-3-yl)pyrimidin-2-amine’ scaffold of Imatinib has been designed and synthesized. A selected group from the target compounds was tested over a panel of 60 cancer cell lines at a single dose concentration of 10 μM, and the two most active compounds, 25b and 30, were further tested in a five-dose testing mode to determine their IC 50 values over the 60 cell lines. Compound 30 has showed good potencies and high efficacies, and was accordingly tested at a single dose concentration of 10 μM over a panel of 54 kinases. At this concentration, the compound has showed multiple inhibitions over a number of oncogenic kinases, including ABL1, AKT1, LCK, C-SRC, PIM1, FLT3, FYN, and KDR. A molecular modeling study was made by docking of the most active compound 30 and its inactive analog 29 into the kinase domain of ABL1 to investigate their possible binding interactions.