Imidazole-4,5-dicarboxamide derivatives with antiproliferative activity against HL-60 cells.
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.
Perchellet
Elisabeth M
EM
Anti-Cancer Drug Laboratory, Kansas State University, Division of Biology, Ackert Hall, Manhattan, Kansas 66506-4901, USA.
Perchellet
Jean-Pierre
JP
Baures
Paul W
PW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D007093:Imidazoles; D000255:Adenosine Triphosphate; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2