Isoprenoid biosynthesis via the methylerythritol phosphate pathway: structural variations around phosphonate anchor and spacer of fosmidomycin, a potent inhibitor of deoxyxylulose phosphate reductoisomerase.
Fosmidomycin and its analogue FR-900098 are potent inhibitors of 1-deoxy-d-xylulose 5-phosphate reducto-isomerase (DXR), the second enzyme of the MEP pathway for the biosynthesis of isoprenoids. This paper describes the synthesis of analogues of the two reverse phosphonohydroxamic acids 3 and 4, in which the length of the carbon spacer is modified, the N-methyl group of 3 is replaced by an ethyl group, and the phosphate group is replaced by potential isosteric moieties, i.e., sulfonate or carboxylate functionalities. The potential of the synthesized analogues to inhibit the E. coli DXR was evaluated.
Zinglé
Catherine
C
Université de Strasbourg/CNRS, Strasbourg, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67070 Strasbourg, France.
Kuntz
Lionel
L
Tritsch
Denis
D
Grosdemange-Billiard
Catherine
C
Rohmer
Michel
M
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004896:Erythritol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000737:chemistry*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013403:Sugar Phosphates / Q000737:chemistry / Q000378:metabolism*; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
C114232:2-C-methylerythritol 4-phosphate; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D063065:Organophosphonates; D013403:Sugar Phosphates; D013729:Terpenes; D005578:Fosfomycin; C024640:fosmidomycin; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases; D004896:Erythritol