Organic Letters
Letter
component trafficking and turnover (Figure S15). Previously, an
oxime ligation-based method used 10 mM aniline as the catalyst
and a higher concentration (100 μM) of the labeling probe and
required an incubation time of 90 min to achieve efficient cell
labeling.9 Our method does not need a catalyst and requires a
lower concentration (20 μM) of the probes and shorter labeling
time (30 min). These are desirable features of a biocompatible
method to label, monitor, and track the molecules on the cell
membranes.
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In summary, we have shown that the condensation between 2-
aminoethanethioamide and an aldehyde is highly chemose-
lective. It was successfully utilized to site-selectively label
peptides, proteins, and living cells. The reaction proceeds
smoothly in an aqueous buffer under mild conditions, uses very
low reactant concentrations, and does not require any catalysts
or reducing agents that might be toxic to living systems. The
thiazolidin-5-imine linkage so-formed is stable at physiological
and weakly basic pH, while hydrolyzable in acidic media (e.g.,
pH 4.5). Such a property of pH-dependent stability and
reversibility would be useful for drug delivery purpose.10 It is
noteworthy that a related thiazolidine ring formed between the
1,2-aminothiol moiety of an N-terminal Cys residue and an
aldehyde is not very stable under physiological pH but rather
stable in slightly acidic pH.11 As another favorable characteristic
of this new method, the 2-aminoethanethioamide moiety can be
easily installed in any compounds and is very stable in air. On the
contrary, the 1,2-aminothiol moiety required for thiazolidine
formation is very prone to oxidation in which the thiol is
oxidized to disulfide.12 Aldehyde is one of the most extensively
utilized bioconjugation functionalities, and many chemical and
enzymatic methods are available to introduce an aldehyde group
into proteins at either a terminal or internal site.6,13 Therefore,
we anticipate that this new condensation reaction will be an
attractive alternative to the currently used bioconjugation
techniques for a wide range of applications in the future.
́
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
Experimental procedures and characterization data
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̈
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AUTHOR INFORMATION
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(12) Bermejo-Velasco, D.; Nawale, G. N.; Oommen, O. P.; Hilborn,
J.; Varghese, O. P. Chem. Commun. 2018, 54, 12507.
Corresponding Author
ORCID
(13) (a) Wu, P.; Shui, W.; Carlson, B. L.; Hu, N.; Rabuka, D.; Lee, J.;
Bertozzi, C. R. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 3000.
(b) Rabuka, D.; Rush, J. S.; deHart, G. W.; Wu, P.; Bertozzi, C. R. Nat.
Protoc. 2012, 7, 1052. (c) Tuley, A.; Lee, Y. J.; Wu, B.; Wang, Z. Y.; Liu,
W. S. Chem. Commun. 2014, 50, 7424. (d) Bi, X. B.; Pasunooti, K. K.;
Lescar, J.; Liu, C. F. Bioconjugate Chem. 2017, 28, 325. (e) El-Mahdi, O.;
Melnyk, O. Bioconjugate Chem. 2013, 24, 735. (f) Spears, R. J.;
Brabham, R. L.; Budhadev, D.; Keenan, T.; McKenna, S.; Walton, J.;
Brannigan, J. A.; Brzozowski, A. M.; Wilkinson, A. J.; Plevin, M.;
Fascione, M. A. Chem. Sci. 2018, 9, 5585. (g) Howard, T. S.; Cohen, R.
D.; Nwajiobi, O.; Muneeswaran, Z. P.; Sim, Y. E.; Lahankar, N. N.; Yeh,
J. T.; Raj, M. Org. Lett. 2018, 20, 5344.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This research is supported by A*STAR (ETPL-QP-19-06) and
the Ministry of Education (NGF-2017-03-040; MOE 2016-T3-
1-003) of Singapore and by the Singapore National Research
Foundation under its Antimicrobial Resistance IRG adminis-
tered by the Singapore-MIT Alliance for Research and
Technology.
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