New aromatic inhibitors of EPSP synthase incorporating hydroxymalonates as novel 3-phosphate replacements.
A new, aromatic analogue of the EPSP synthase enzyme reaction intermediate 1 has been identified, which contains a 3-hydroxymalonate moiety in place of the usual 3-phosphate group. This simplified inhibitor was readily prepared in five steps from ethyl 3,4-dihydroxybenzoate. The resulting tetrahedral intermediate mimic 9 is an effective, competitive inhibitor versus S3P with an apparent Ki of 0.57 +/- 0.06 microM. This result demonstrates that 3-hydroxymalonates exhibit potencies comparable to aromatic inhibitors containing the previously identified 3-malonate ether replacements and can thus function as suitable 3-phosphate mimics in this system. These new compounds provide another example in which a simple benzene ring can be used effectively in place of the more complex shikimate ring in the design of EPSP synthase inhibitors. Furthermore, the greater potency of 9 versus the glycolate derivative 10 and the 5-deoxy-analog 11, again confirms the requirement for multiple anionic charges at the dihydroxybenzoate 5-position in order to attain effective inhibition of this enzyme.
Shah
A
A
Ceregen Corporate Research, Unit of Monsanto Company, St. Louis, MO 63198, USA.
Font
J L
JL
Miller
M J
MJ
Ream
J E
JE
Walker
M C
MC
Sikorski
J A
JA
D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase; D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010710:Phosphates / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013646:Tartronates / Q000737:chemistry*; D014166:Transferases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D010710:Phosphates; D011994:Recombinant Proteins; D013646:Tartronates; C032973:tartronic acid; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase