ORGANIC
LETTERS
2009
Vol. 11, No. 20
4708-4711
Synthesis of Novel Peptide Linkers:
Simultaneous Cyclization and Labeling
Gajanan K. Dewkar, Pedro B. Carneiro, and Matthew C. T. Hartman*
Department of Chemistry and Massey Cancer Center, Virginia Commonwealth
UniVersity, 401 College Street, Richmond, Virginia 23298-0037
mchartman@Vcu.edu
Received July 21, 2009
ABSTRACT
Synthesis of novel peptide linkers was accomplished by monocarboxylation of 1,3,5-tris(bomomethyl)benzene with a wide variety of carboxylic
acids in the presence of diisopropylethylamine. These reagents can be used to simultaneously cyclize and label peptides containing two
cysteines. Many labels are compatible with this method including lipids, fluorescent groups, and biotin.
Cyclic peptides are widely produced in nature1 and possess
a broad range of biological activities. Cyclization leads to
enhanced metabolic stability2 and may lead to increased
specificity2c,3 or affinity4 due to the imposed conformational
constraints.5 In specific cases, cyclization can also lead to
enhanced cell permeability.2b,6 These properties make cyclic
peptides promising candidates for the development of new
therapeutic agents.7
However, cyclization also complicates the synthesis of
peptides since selective, orthogonal protecting groups are
typically required to unmask the reactive functional groups
used in the cyclization.8 The yields and rates of cyclization
reactions can also be highly variable,9 further complicating
their synthesis. Where the construction of cyclic peptide
libraries is concerned, or if the peptide needs to be both
cyclized and labeled, these problems become even more
acute.
Recently, a highly chemoselective strategy for peptide
cyclization has been developed which involves treating linear
unprotected dicysteine-containing peptides with R,R′-dibro-
moxylenes, leading to a stable bis-thioether linkage (Scheme
1).10 This reaction was found to be high yielding and
relatively independent of ring size or functional groups,
making it an ideal strategy for cyclization. Furthermore, by
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Chem. Biol. 2007, 2, 625–634. (b) Gudmundsson, O. S.; Pauletti, G. M.;
Wang, W.; Shan, D.; Zhang, H.; Wang, B.; Borchardt, R. T. Pharm. Res.
1999, 16, 7–15. (c) Piserchio, A.; Salinas, G. D.; Li, T.; Marshall, J.; Spaller,
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(4) Khan, A. R.; Parrish, J. C.; Fraser, M. E.; Smith, W. W.; Bartlett,
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(5) Hruby, V. J.; al-Obeidi, F.; Kazmierski, W Biochem. J. 1990, 268,
249–262.
(8) For examples, see: (a) Liu, T.; Joo, S. H.; Voorhees, J. L.; Brooks,
C. L.; Pei, D. Bioorg. Med. Chem. 2009, 17, 1026–1033. (b) Walker, M. A.;
Johnson, T. Tetrahedron Lett. 2001, 42, 5801–5804. (c) Lundquist, J. T. t.;
Pelletier, J. C. Org. Lett. 2002, 4, 3219–3221. (d) Lawrence, J.; Jourdan,
M.; Vallee, Y.; Blandin, V. Org. Biomol. Chem. 2008, 6, 4575–4581.
(9) (a) Davies, J. S. J. Pept. Sci. 2003, 9, 471–501. (b) Fluxa, V. S.;
Reymond, J. L. Bioorg. Med. Chem. 2009, 17, 1018–1025.
(6) (a) Kwon, Y. U.; Kodadek, T. Chem. Biol. 2007, 14, 671–677. (b)
Rezai, T.; Yu, B.; Millhauser, G. L.; Jacobson, M. P.; Lokey, R. S. J. Am.
Chem. Soc. 2006, 128, 2510–2511
.
(7) (a) Katsara, M.; Tselios, T.; Deraos, S.; Deraos, G.; Matsoukas,
M. T.; Lazoura, E.; Matsoukas, J.; Apostolopoulos, V. Curr. Med. Chem.
2006, 13, 2221–2232. (b) Willey, J. M.; van der Donk, W. A. Annu. ReV.
Microbiol. 2007, 61, 477–501.
(10) Timmerman, P.; Beld, J.; Puijk, W. C.; Meloen, R. H. ChemBio-
Chem 2005, 6, 821–824.
10.1021/ol901662c CCC: $40.75
Published on Web 09/08/2009
2009 American Chemical Society