1476 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 5
Crane and Boger
123, 1862–1871. (f) Crowley, B. M.; Mori, Y.; McComas, C. C.; Tang,
D.; Boger, D. L. Total Synthesis of the Ristocetin Aglycon. J. Am.
Chem. Soc. 2004, 126, 4310–4317. (g) Boger, D. L. Vancomycin,
Teicoplanin, and Ramoplanin: Synthetic and Mechanistic Studies. Med.
Res. ReV. 2001, 21, 356–381.
2-bromophenylhydrazine with triethylamine (Et3N) at 70 °C did
provide the desired acylated hydrazines (data not shown).
Conclusions
(5) Cristofaro, M. F.; Beauregard, D. A.; Yan, H.; Osborn, N. J.; Williams,
D. H. Cooperativity between Non-Polar and Ionic Forces in the
Binding of Bacterial Cell Wall Analogues by Vancomycin in Aqueous
Solution. J. Antibiot. 1995, 48, 805–810.
(6) (a) Booth, P. M.; Stone, D. J. M.; Williams, D. H. The Edman
Degradation of Vancomycin: Preparation of Vancomycin Hexapeptide.
J. Chem. Soc., Chem. Commun. 1987, 1694–1695. (b) Booth, P. M.;
Williams, D. H. Preparation and Conformational Analysis of Vanco-
mycin Hexapeptide and Aglucovancomycin Hexapeptide. J. Chem.
Soc., Perkin Trans. 1 1989, 2335–2339.
(7) (a) Gerber, P. R.; Mu¨ller, K. MAB, a Generally Applicable Molecular
Force Field for Structure Modelling in Medicinal Chemistry. J. Com-
put.-Aided Mol. Des 1995, 9, 251–268. (b) Gerber Molecular Design.
K.; Hanamaki, S.; Fujisawa, I.; Aoki, K. Crystal Structures of the
Complexes between Vancomycin and Cell-Wall Precursor Analogs.
J. Mol. Biol., in press.
A series of N-terminal derivatives of the vancomycin aglycon
were prepared replacing the residue 1 N-methyl D-leucyl amino
acid with a series of N-methyl D-amino acids bearing H-bond
donor or reactive nucleophilic substituents. An examination of
their antimicrobial activity against vancomycin-sensitive and
vancomycin-resistant bacteria and their affinity for model ligands
2 and 3 incorporating D-Ala-D-Ala and D-Ala-D-Lac did not
reveal evidence of significant enhancements in activity or
affinity, including those capable of formation of covalent adducts
derived from their reaction with ligand 3 bearing an ester.
Whether this reflects the limitations of our original designs or
features of binding not yet recognized is unknown but is a topic
of our continuing studies.
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (Grant CA 41101), Dr.
G. Boldt for supplying gram quantities of vancomycin aglycon,
and Professor K. D. Janda for the use of the HF apparatus.
(8) (a) All molecular graphics images were produced using the UCSF
Chimera package from the Resource for Biocomputing, Visualization,
and Informatics at the University of California, San Francisco
(supported by Grant NIH P41 RR-01081). For details, see the
following: (b) Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch,
G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF ChimerasA
Visualization System for Exploratory Research and Analysis. J. Com-
put. Chem. 2004, 25, 1605–1612. (c) Chimera home page can be found
Supporting Information Available: Compounds 5 and 16 were
prepared according to published procedures.6,14 Full experimental
details and characterization for all new intermediates and final
compounds are provided in the supporting information. This material
(9) Kahne, D.; Walker, S.; Silva, D. J. Desleucyl Glycopeptide Antibiotics
and Methods of Making Same. Patent WO 2000/59528 (US
2004110665), 2000.
(10) Kim, S. J.; Matsuoka, S.; Patti, G. J.; Schaefer, J. Vancomycin
Derivative with Damaged D-Ala-D-Ala Binding Cleft Binds to Cross-
Linked Peptidoglycan in the Cell Wall of Staphylococcus aureus.
Biochemistry 2008, 47, 3822–3831.
References
(1) For reviews see the following: (a) Kahne, D.; Leimkuhler, C.; Lu,
W.; Walsh, C. T. Glycopeptide and Lipoglycopeptide Antibiotics.
Chem. ReV. 2005, 105, 428–448. (b) Hubbard, B. K.; Walsh, C. T.
Vancomycin Assembly: Nature’s Way. Angew. Chem., Int. Ed. 2003,
42, 730–765. (c) Williams, D. H.; Bardsley, B. The Vancomycin Group
of Antibiotics and the Fight against Resistant Bacteria. Angew. Chem.,
Int. Ed. 1999, 38, 1172–1193. (d) Malabarba, A.; Nicas, T. I.;
Thompson, R. C. Structural Modifications of Glycopeptide Antibiotics.
Med. Res. ReV. 1997, 17, 69–137.
(11) Hunt, A. H.; Marconi, G. G.; Elzey, T. K.; Hoehn, M. M. N-
Demethylvancomycin. J. Antibiot. 1984, 37, 917–919.
(12) Pavlov, A. Y.; Berdnikova, T. F.; Olsufyeva, E. N.; Lazhko, E. I.;
Malkova, I. V.; Preobrazhenskaya, M. N. Synthesis and Biological
Activity of Derivatives of Glycopeptide Antibiotics Eremomycin and
Vancomycin Nitrosated, Acylated, or Carbamoylated at the N-
Terminal. J. Antibiot. 1993, 46, 1731–1739.
(13) Gale, T. F.; Go¨rlitzer, J.; O’Brien, S. W.; Williams, D. H. The Synthesis
and Binding of N-Terminal Derivatives of Vancomycin to a Bacterial
Cell Wall Analogue. J. Chem. Soc., Perkin Trans. 1 1999, 2267–2270.
(14) Wanner, J.; Tang, D.; McComas, C. C.; Crowley, B. M.; Jiang, W.; Moss,
J.; Boger, D. L. A New and Improved Method for Deglycosylation of
Glycopeptide Antibiotics Exemplified with Vancomycin, Ristocetin, and
Ramoplanin. Bioorg. Med. Chem. Lett. 2003, 13, 1169–1173.
(15) Cheung, S. T.; Benoiton, N. L. N-Methylamino Acids in Peptide
Synthesis. V. The Synthesis of N-tert-Butyloxycarbonyl,N-Methyl-
amino Acids by N-methylation. Can. J. Chem. 1997, 55, 906–910.
(16) Drake, B.; Patek, M.; Lebl, M. A Convenient Preparation of Mono-
substituted N,N′-di(Boc)-Protected Guanidines. Synthesis 1994, 6, 579–
582.
(2) For reviews on glycopeptide resistance see the following: (a) Mala-
barba, A.; Ciabatti, R. Glycopeptide Derivatives. Curr. Med. Chem.
2001, 8, 1759–1773. (b) Pootoolal, J.; Neu, J.; Wright, G. D.
Glycopeptide Antibiotic Resistance. Annu. ReV. Pharmacol. Toxicol.
2002, 42, 381–408. (c) Van Bambeke, F. V.; Van Laethem, Y.;
Courvalin, P.; Tulkens, P. M. Glycopeptide Antibiotics: From
Conventional to New Derivatives. Drugs 2004, 64, 913–936. (d)
Su¨ssmuth, R. D. Vancomycin Resistance: Small Molecule Approaches
Targeting the Bacterial Cell Wall Biosynthesis. ChemBioChem 2002,
3, 295–298. (e) Gao, Y. Glycopeptide Antibiotics and Development
of Inhibitors to Overcome Vancomycin Resistance. Nat. Prod. Rep.
2002, 19, 100–107. (f) Healy, V. L.; Lessard, I. A.; Roper, D. I.; Knox,
J. R.; Walsh, C. T. Vancomycin Resistance in Enterococci: Repro-
gramming of the D-Ala-D-Ala Ligases in Bacterial Peptidoglycan
Biosynthesis. Chem. Biol. 2000, 7, R109–R119.
(17) Armstrong, A.; Jones, L. H.; Knight, J. D.; Kelsey, R. D. Oxaziridine-
Mediated Amination of Primary Amines: Scope and Application to a
One-Pot Pyrazole Synthesis. Org. Lett. 2005, 7, 713–716.
(3) McComas, C. C.; Crowley, B. M.; Boger, D. L. Partitioning the Loss
in Vancomycin Binding Affinity for D-Ala-D-Lac into Lost H-Bond
and Repulsive Lone Pair Contributions. J. Am. Chem. Soc. 2003, 125,
9314–9315.
(18) Antimicrobial assays were run as previously described: (a) McComas,
C. C.; Crowley, B. M.; Hwang, I.; Boger, D. L. Synthesis and
Evaluation of Methyl Ether Derivatives of Vancomycin, Teicoplanin,
and Ristocetin Aglycon Methyl Ethers. Bioorg. Med. Chem. Lett. 2003,
13, 2933–2936. (b) McAtee, J. J.; Castle, S. L.; Jin, Q.; Boger, D. L.
Synthesis and Evaluation of Vancomycin and Vancomycin Aglycon
Analogues That Bear Modifications in the Residue 3 Asparagine.
Bioorg. Med. Chem. Lett. 2002, 12, 1319–1322.
(19) UV-difference titration assays were run as previously described: (a)
Nieto, M.; Perkins, H. R. The Specificity of Combination between
Ristocetins and Peptides Related to Bacterial Cell Wall Mucopeptide
Precursors. Biochem. J. 1971, 124, 845–852. (b) Nieto, M.; Perkins,
H. R. Physiochemical Properties of Vancomycin and Iodovancomycin
and Their Complexes with Diacetyl-L-lysyl-D-alanyl-D-alanine. Bio-
chem. J. 1971, 123, 773–787. (c) Perkins, H. R. Specificity of
Combination between Mucopeptide Precursors and Vancomycin or
Ristocetin. Biochem. J. 1969, 111, 195–205.
(4) (a) Crowley, B. M.; Boger, D. L. Total Synthesis and Evaluation of
[Ψ[CH2NH]Tpg4]Vancomycin Aglycon: Reengineering Vancomycin
for Dual D-Ala-D-Ala and D-Ala-D-Lac Binding. J. Am. Chem. Soc.
2006, 128, 2885-2892. For related synthetic efforts, see the
following: (b) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.;
Loiseleur, O.; Castle, S. L. Diastereoselective Total Synthesis of the
Vancomycin Aglycon with Ordered Atropisomer Equilibrations. J. Am.
Chem. Soc. 1999, 121, 3226–3227. (c) Boger, D. L.; Miyazaki, S.;
Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. Total
Synthesis of the Vancomycin Aglycon. J. Am. Chem. Soc. 1999, 121,
10004–10011. (d) Boger, D. L.; Kim, S. H.; Miyazaki, S.; Strittmatter,
H.; Weng, J.-H.; Mori, Y.; Rogel, O.; Castle, S. L.; McAtee, J. J.
Total Synthesis of the Teicoplanin Aglycon. J. Am. Chem. Soc. 2000,
122, 7416–7417. (e) Boger, D. L.; Kim, S. H.; Mori, Y.; Weng, J.-
H.; Rogel, O.; Castle, S. L.; McAtee, J. J. First and Second Generation
Total Synthesis of the Teicoplanin Aglycon. J. Am. Chem. Soc. 2001,
JM801549B