Synthesis and MEK1 inhibitory activities of imido-Substituted 2-chloro-1,4-naphthoquinones

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 μM. 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. 2-Chloro-3-( N-succinimidyl)-1,4-naphthoquinone 6 was found to be a selective inhibitor of MEK1 with an IC 50 of 0.38 μM, while an open-chain homologue 10 showed selective cytotoxicity against renal cancer cell lines in the NCI in vitro tumor screening.