Edward M. Burgess

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 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.

Synthesis of 3-[(N-carboalkoxy)ethylamino]-indazole-dione derivatives and their biological activities on human liver carbonyl reductase.

A series of indazole-dione derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of appropriate substituted benzoquinones or naphthoquinones and N-carboalkoxyamino diazopropane derivatives. These compounds were evaluated for their effects on human carbonyl reductase. Several of the analogs were found to serve as substrates for carbonyl reductase with a wide range of catalytic efficiencies, while four analogs display inhibitory activities with IC(50) values ranging from 3-5 microM. Two of the inhibitors were studied in greater detail and were found to be noncompetitive inhibitors against both NADPH and menadione with K(I) values ranging between 2 and 11 microM. Computational studies suggest that conformation of the compounds may determine whether the indazole-diones bind productively to yield product or nonproductively to inhibit the enzyme.

A Novel Route to an Aza Analog of the Marine Natural Product Damirone B

Abstract 3-(N-carboalkoxyamino)-1-diazopropane has been used as a difunctional synthon for a three step synthesis of pyrazolo[5,4,3-de]-1,2,3,6,7-pentahydroquinolin-6,7-dione, a tricyclic aza analog of the marine natural product Damirone B.

New N-substituted (±)-dehydronorglaucine analogs

Abstract The aporphine alkaloid N-carbethoxydehydronorglaucine (1) was found to have promising in vitro antitumor activity, but poor water solubility. We report the synthesis of 1, the efficient hydrolysis of its urethane group and the further transformation into several new dehydronorglaucine analogs.