Journal of the American Chemical Society
Communication
resin (see: Supporting Information). We also note that the
amino group of DTBA enables its covalent attachment to a
soluble molecule, resin, or surface by simple reactions, such as
reductive amination (which preserves the cationic charge) or
N-acylation. We conclude that the attributes of DTBA could
enable it to supplant DTT as the preferred reagent for reducing
disulfide bonds in biomolecules.
(7) Tris(2-carboxyethyl)phosphine (TCEP) is more potent than
2e
DTT at reducing disulfide bonds between small molecules but not
2
l
within proteins.
(
8) Another commercial dithiol, bis(2-mercaptoethyl) sulfone
2g
(
BMS), has low thiol pK values of 7.9 ± 0.2 and 9.0 ± 0.2. Upon
a
oxidation, however, BMS forms a seven-membered ring with E°′ =
−0.291 ± 0.002) V (Figure S3), making BMS a less potent reducing
agent than DTT.
9) (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis:
(
(
Construction of Chiral Molecules Using Amino Acids; John Wiley & Sons:
New York, NY, 1987. (b) McCaldon, P.; Argos, P. Proteins 1988, 4,
ASSOCIATED CONTENT
■
*
S
Supporting Information
9
9−122.
(10) Carbamate derivatives of DTBA are known. (a) Kessler, P.;
Servent, D.; Hirth, C. Tetrahedron Lett. 1994, 35, 7237−7240.
b) Servent, D.; Menez, A.; Kessler, P. FEBS Lett. 1995, 360, 261−265.
11) Mitsunobu, O.; Masahiko, E. Bull. Chem. Soc. Jpn. 1971, 44,
3427−3430.
12) Jencks, W. P.; Salvesen, K. J. Am. Chem. Soc. 1971, 93, 4433−
436.
13) Connett, P. H.; Wetterhahn, K. E. J. Am. Chem. Soc. 1986, 108,
(
́
(
AUTHOR INFORMATION
(
4
(
Notes
1842−1847.
The authors declare no competing financial interest.
(14) Lees, W. J.; Whitesides, G. M. J. Org. Chem. 1993, 58, 642−647.
(15) (a) Benesch, R. E.; Benesch, R. J. Am. Chem. Soc. 1955, 77,
5
877−5881. (b) Woycechowsky, K. J.; Wittrup, K. D.; Raines, R. T.
ACKNOWLEDGMENTS
■
Chem. Biol. 1999, 6, 871−879.
(16) The amino group of DTBA is assumed to be cationic
throughout its pH-titration, as cysteamine has an amino pK of
We are grateful to Professor W. W. Cleland and S. B. Johnston
for enabling advice, and to N. McElfresh for preliminary work
on this project. M.J.P. was supported by Molecular and Cellular
Pharmacology Training Grant T32 GM008688 (NIH) and
predoctoral fellowship 09PRE2260125 (American Heart
Association). This work was supported by Grant R01
GM044783 (NIH).
a
1
3
1
(
3
(
0.44.
17) Chivers, P. T.; Prehoda, K. E.; Raines, R. T. Biochemistry 1997,
6, 4061−4066.
18) (a) Roberts, D. D.; Lewis, S. D.; Ballou, D. P.; Olson, S. T.;
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W. A.; Collinson, A. R. Anal. Biochem. 1993, 213, 49−56.
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19) (a) Schechter, I.; Berger, A. Biochem. Biophys. Res. Commun.
1
967, 27, 157−162. (b) Pickersgill, R. W.; Harris, G. W.; Garman, E.
Acta Crystallogr., Sect. B 1992, 48, 59−67.
20) Rao, J. K. M.; Bujacz, G.; Wlodawer, A. FEBS Lett. 1998, 439,
33−137.
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2f,3a,d
(
4) βME is also an unstable, foul-smelling liquid
with a high
reduction potential and high thiol pK (Table 1).
a
(
5) Evans, R. M.; Fraser, J. B.; Owen, L. N. J. Chem. Soc. 1947, 248−
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6) The current price of DTT is 10 -fold greater per thiol group than
that of βME (Sigma−Aldrich, St. Louis, MO).
2
(
2
4
059
dx.doi.org/10.1021/ja211931f | J. Am. Chem. Soc. 2012, 134, 4057−4059