Synthesis and cytotoxic activity of 2-methylimidazo[1,2-a]pyridine- and quinoline-substituted 2-aminopyrimidine derivatives.

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Vilchis-Reyes MA, Zentella A, Martinez-Urbina MA, Guzman A, Vargas O, Ramirez Apan MT, Ventura Gallegos JL, Diaz E

Synthesis and cytotoxic activity of 2-methylimidazo[1,2-a]pyridine- and quinoline-substituted 2-aminopyrimidine derivatives.

Eur J Med Chem. 2010 Jan;45(1):379-86. doi: 10.1016/j.ejmech.2009.10.002. Epub 2009 Oct 13.

PubMed ID

19879023 [ View in PubMed

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Abstract

A series of 2-methylimidazo[1,2-a]pyridine- and quinoline-substituted 2-aminopyrimidines derivatives were synthesized using a convenient synthetic route. We evaluate the isosteric replacement of methyl groups in 4-(2-methylimidazo[1,2-a]pyridin-3-yl)-N-p-tolylpyrimidin-2-amine (compound 1) by trifluoromethyl groups and the isosteric substitution of the 2-methylimidazo[1,2-a]pyridin-3-yl scaffold by quinolin-4-yl or quinolin-3-yl moieties. The replacement of hydrogen by fluorine does not affect notably the cytotoxic activity and CDK inhibitor activity in this series. Quinolin-4-yl-substituted compound, 8, presents cytotoxic activity and is most effective and selective against CDK1/CycA than against CDK2/CycB. Compound 11, which has a quinolin-3-yl moiety is CDK inhibitor but presents null cytotoxic activity. Quinolin-4-yl-substituted compounds constitute a new lead of cytotoxic and CDK inhibitor compounds from which more compelling and selective inhibitors can be designed.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Olomoucine	Cyclin-dependent kinase 1	IC 50 (nM)	7000	N/A	N/A	Details