naphthoquinones and malonic-acid

CDC25 phosphatases are considered as attractive targets for anti-cancer therapy. To date, quinone derivatives are among the most potent inhibitors of CDC25 phosphatase activity. We present in this paper the synthesis and the biological evaluation of new quinolinedione and naphthoquinone derivatives, containing carboxylic or malonic acids groups introduced to mimic the role of the phosphate moieties of Cyclin-Dependent Kinase complexes. The most efficient compounds show inhibitory activity against CDC25B with IC(50) values in the 10 microM range, and are cytotoxic against HeLa cells.

Topics: Antineoplastic Agents; Carboxylic Acids; cdc25 Phosphatases; Cyclin-Dependent Kinases; Enzyme Inhibitors; HeLa Cells; Humans; Inhibitory Concentration 50; Malonates; Molecular Mimicry; Naphthoquinones; Phosphates; Quinolones; Structure-Activity Relationship

Cytochrome P450 158A2 (CYP158A2) can polymerize flaviolin to red-brown pigments, which may afford physical protection to the organism, possibly against the deleterious effects of UV radiation. We have found that the small molecule malonic acid enables cocrystallization of this mixed function oxidase with the azole inhibitor 4-phenylimidazole. The presence of malonate molecules affects the behavior of the binding of 4-phenylimidazole to CYP158A2 and increases inhibition potency up to 2-fold compared to 4-phenylimidazole alone. We report here the crystal structure of the 4-phenylimidazole/malonate complex of CYP158A2 at 1.5 A. Two molecules of malonate used in crystallization are found above the single inhibitor molecule in the active site. Those two molecules are linked between the BC loop and beta 1-4/beta 6-1 strands via hydrogen bond interactions to stabilize the conformational changes of the BC loop and beta strands that take place upon inhibitor binding compared to the ligand-free structure we have reported previously. 4-Phenylimidazole can launch an extensive hydrogen-bonding network in the region of the F/G helices which may stabilize the conformational changes. Our findings clearly show that two molecules of malonate assist the inhibitor 4-phenylimidazole to assume a specific location producing more inhibition in the enzyme catalytic activity.

Topics: Binding Sites; Crystallization; Cytochrome P-450 Enzyme Inhibitors; Escherichia coli; Hydrogen Bonding; Imidazoles; Kinetics; Ligands; Malonates; Mixed Function Oxygenases; Models, Molecular; Naphthoquinones; Protein Conformation; Protein Structure, Secondary; Streptomyces coelicolor

1. The following compounds, added to the growth medium of Fusarium javanicum, were converted into labelled javanicin with the percentage incorporations noted in parentheses: [Me-(14)C]methionine (0.83); [1-(14)C]acetate (0.70); [2-(14)C]malonate (0.07). 2. Labelled samples of javanicin were degraded by Zeisel reaction, Kuhn-Roth oxidation and reaction with sodium hypoiodite; acetic acid obtained from the Kuhn-Roth reaction was further degraded by the Schmidt reaction. Labelled methionine was used only for the formation of the methoxyl group, and the remaining carbon atoms were derived by the acetate-plus-polymalonate pathway. The methyl group attached directly to the naphthaquinone ring is derived by the reduction of a carboxyl group. 3. The demonstration of this biosynthetic pathway supports the assignment of the methoxyl group at position 7.

Topics: Acetates; Acetic Acid; Carbon; Chromatography; Culture Media; Fungi; Fusarium; Malonates; Metabolism; Methionine; Naphthoquinones; Oxidation-Reduction; Pigments, Biological; Research