Parallel synthesis of a library of symmetrically- and dissymmetrically-disubstituted imidazole-4,5-dicarboxamides bearing amino acid esters.
A series of N,N'-disubstituted imidazole-4,5-dicarboxamides (I45DCs) were prepared and tested in order to determine their antiproliferative activity against HL-60 cells. The design of the I45DCs was based in part on the structures of trisubstituted purines complexed with cyclin dependent kinase 2 (cdk2), a protein important in regulating the G1/S transition in the cell cycle, and the intramolecular hydrogen bond in I45DCs that predisposes the conformation to one that mimics substituted adenosines. A majority of the I45DCs in this study inhibit proliferation of HL-60 cells as measured by an MTS mitochondrial functional assay with IC50's in the 2.5-25 microM range. The SAR of the I45DCs is consistent with anticipated hydrogen bonding interactions in the ATP-binding site of cdk2. Thus, the I45DCs represent a useful scaffold for anticancer lead discovery that is both readily accessible and easily diversified.