ORGANIC
LETTERS
2003
Vol. 5, No. 4
539-541
Synthesis of a Carbohydrate-Derived
Hydroxamic Acid Inhibitor of the
Bacterial Enzyme (LpxC) Involved in
Lipid A Biosynthesis
,†
Xuechen Li,† Taketo Uchiyama,†,‡ Christian R. H. Raetz,§ and Ole Hindsgaul*
Department of Chemistry, UniVersity of Alberta, Edmonton, AB T6G 2G2, Canada,
College of Pharmacy, Nihon UniVersity, Chiba 274-0063, Japan, and Department of
Biochemistry, Duke UniVersity Medical Center, Durham, North Carolina 27710
Received December 12, 2002
ABSTRACT
The enzyme LpxC (UDP-3-O-[(R)-3-hydroxymyristoyl]-GlcNAc deacetylase) catalyzes the second step of lipid A biosynthesis and is essential
for bacterial growth. A GlcNAc-derived hydroxamic acid inhibitor 8 of this enzyme was synthesized using two different routes. Compound 8
exhibits activity toward LpxC enzymes from a wider spectrum of bacterial species than any of the previously reported hydroxamic acid
inhibitors.
The clinical efficacy of many existing antibiotics is being
threatened by the emergence of multidrug-resistant bacterial
pathogens. There is an urgent need for compounds that act
on novel molecular targets that circumvent the established
resistance mechanisms. Gram-negative bacteria, which are
responsible for a large number of infectious diseases, have
unique outer membranes that contain lipopolysaccharides
(LPS). Agents interfering with the biosynthesis of LPS are
often bactericidal or bacteriostatic.1
The hydrophobic anchor part of the LPS molecule is called
lipid A. Recent studies2 have shown that the enzymes
involved in the biosynthesis of lipid A are suitable pharma-
ceutical targets. Many of these enzymes are both unique and
essential to Gram-negative bacteria. The enzyme LpxC is
one example: it catalyzes the second step in lipid A
biosynthesis (Scheme 1). LpxC has been identified in more
than 40 Gram-negative species.3
In 1996, Merck scientists reported the discovery that
hydroxamic acids, derivatized with hydrophobic aromatic
moieties, could inhibit LpxC from E. coli. These inhibitors
were shown to bind competitively to a zinc ion of the
enzyme.4,5 We now report the synthesis of compound 8
(Scheme 2), which is a carbohydrate-derived hydroxamic
acid where the carbohydrate part resembles the natural
substrate of the LpxC enzyme: UDP-3-O-[(R)-3-hydroxy-
(3) Kline, T.; Andersen, N. H.; Harwood: E. A.; Bowman, J.; Malanda,
A.; Endsley, S.; Erwin, A. L.; Doyle, M.; Fong, S.; Harris, A. L.;
Mendelsohn, B.; Mdluli, K.; Raetz, C. R. H.; Stover, C. K.; Witte, P. R.;
Yabannavar, A.; Zhu, S. J. Med. Chem. 2002, 45, 3112.
(4) Onishi, H. R.; Pelak, B. A.; Gerchens, L. S.; Silver, L. L.; Kahan, F.
M.; Chen, M.; Patchett, A. A.; Galloway, S. M.; Hyland, S. A.; Anderson,
M. S.; Raetz, C. R. H. Science 1996, 274, 980.
† University of Alberta.
‡ Nihon University.
§ Duke University Medical Center.
(1) Ritter, T. K.; Wong, C.-H. Angew. Chem., Int. Ed. 2001, 40, 3508.
(2) (a) Raetz, C. R. H. J. Bacteriol. 1993, 175, 5745. (b) Galloway, S.
M.; Raetz, C. R. H. J. Biol. Chem. 1990, 265, 6394. (c) Kelly, T. M.;
Stachula, S. A.; Raetz, C. R. H.; Anderson, M. S. J. Biol. Chem. 1993,
268, 19866.
(5) Jackman, J. E.; Raetz, C. R. H.; Fierke, C. A. Biochemistry 1999,
38, 1902.
10.1021/ol027458l CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/25/2003