Inhibitors designed for the active site of dihydroorotase.

abstract

• Four new compounds have been synthesized as potential inhibitors of dihydroorotase from Escherichia coli. NMR spectroscopy was used to show that 4,6-dioxo-piperidine-2(S)-carboxylic acid (3), exists in solution as a mixture of the hydrate (7), enol (8), and enolate (9) tautomeric forms. This compound was found to be a competitive inhibitor versus dihydroorotate and thio-dihydroorotate at pH values of 7-9. The K(i) of 76 microM was lowest at pH7.0 where the ketone and hydrate forms of the inhibitor 3 predominate in solution. Compound 3 was reduced to the two diastereomeric 4-hydroxy derivatives (4 and 5) and then dehydrated to yield the alkene derivative, 1,2,3,6-tetrahydro-6-oxopyridine-2(S)-carboxylic acid (6). Compounds 4-6 were competitive inhibitors versus thio-dihydroorotate at pH 8.0 with K(i) values of 3.0, 1.6, and 2.3 mM. Dihydroorotase was unable to dehydrate the 4-hydroxy derivative 4 or 5 to the alkene 6 or catalyze the reverse reaction.

authors

• Raushel, Frank

published proceedings

• Bioorg Chem

author list (cited authors)

• Li, Y., & Raushel, F. M.

citation count

• 15

complete list of authors

• Li, Yingchun||Raushel, Frank M

publication date

• January 2005

publisher

• Elsevier  Publisher

published in

• Bioorganic Chemistry  Journal

keywords

• Binding Sites
• Crystallography, X-Ray
• Dihydroorotase
• Enzyme Inhibitors
• Escherichia Coli
• Magnetic Resonance Spectroscopy
• Molecular Structure
• Structure-Activity Relationship

Digital Object Identifier (DOI)

• 10.1016/j.bioorg.2005.08.001

start page

• 470

end page

• 483

volume

• 33

issue

• 6

URL

• http://dx.doi.org/10.1016/j.bioorg.2005.08.001