title: Synthesis and MEK1 inhibitory activities of imido-substituted 2-chloro-1,4-naphthoquinones.
abstract: Mitogen activated protein kinases are of interest as research tools and as therapeutic target for certain physiological disorders. In this study, we found 2-chloro-3-(N-succinimidyl)-1,4-naphthoquinone 6 to be a selective inhibitor of MEK1 with an IC(50) of 0.38 microM. An open-chain homologue, 10, showed selective cytotoxicity against renal cancer in the NCI in vitro tumor screening. Structure-activity relationship study of eight compounds showed the cyclic imido-substituted chloro-1,4-naphthoquinone as more potent and selective MEK1 inhibitors than the open chain homologues. The imido-substituted chloro-1,4-naphthoquinones were synthesized in a straightforward fashion by refluxing 2-amino-3-chloro-1,4-naphthoquinone with the appropriate acid chloride or diacyl dichloride.
authors.affiliation: Department of Chemistry, Howard University, 525 College Street, Washington, DC 20059, USA. obakare@howard.edu
authors.forename: Oladapo
authors.initials: O
authors.lastname: Bakare
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Ashendel
authors.forename: Hairuo
authors.initials: H
authors.lastname: Peng
authors.forename: Leon H
authors.initials: LH
authors.lastname: Zalkow
authors.forename: Edward M
authors.initials: EM
authors.lastname: Burgess
mesh_terms: D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007094:Imides / Q000737:chemistry; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007094:Imides; D009285:Naphthoquinones; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases