ORGANIC
LETTERS
2010
Vol. 12, No. 24
5674-5676
One-Pot Thioether Formation from
S-Nitrosothiols
Dehui Zhang, Nelmi O. Devarie-Baez, Jia Pan, Hua Wang, and Ming Xian*
Department of Chemistry, Washington State UniVersity, Pullman,
Washington 99164, United States
Received October 14, 2010
ABSTRACT
Protein S-nitrosation is an important post-translational modification. However, the detection of S-nitrosation is still problematic because S-nitrosation
products, that is, S-nitrosothiols, are unstable species. Here a new reaction which can selectively convert unstable S-nitrosothiols to stable thioethers
in one-pot under very mild conditions is reported. This reaction has the potential to be applied in the detection of protein S-nitrosation.
Nitric oxide (NO), an endogenous cell signaling agent, is
an important mediator in biological systems. NO-mediated
protein S-nitrosation is a critical post-translational modification
which has strong and dynamic interactions with redox signal-
ing.1 However, currently the detection of S-nitrosation is still a
challenge2 because the products of S-nitrosation, that is,
S-nitrosothiols (SNO), are unstable adducts and methods to
capture fleeting SNO are lacking. We believe that if new
bioorthogonal reactions of SNO can be developed, such
reactions should hold considerable promise for SNO detection.
With this idea in mind, our group has developed a series of
phosphine-based reactions of SNO and proved these reactions
can selectively target SNO and convert unstable SNO to stable
and detectable products.3 In a recent work, triphenylphosphine-
thioester substrates were used to form disulfide conjugates with
SNO in one-step and such a strategy has been successfully
applied to label protein SNO in cell extracts (Scheme 1A).3e
Although the disulfide linkage is sufficiently stable for many
protein analyzing techniques, such as Western blotting, more
stable conjugates than disulfides would be ideal for proteomic
studies of S-nitrosation and for the applications in more complex
biological systems, especially in the presence of free thiols such
as cysteine or glutathione. Herein, we report a reaction which
can selectively convert SNO in one-pot to stable thioether
conjugates.
Inspired by the phosphine-mediated allyl disulfide rear-
rangement developed by Crich and co-workers,4 we designed
a one-pot thioether formation from SNO. As shown in
Scheme 1B, the reaction between phosphine-thioester sub-
strates like 2 and SNO should first generate an aza-ylide
intermediate 3. The reductive ligation process that follows
should then provide a sulfenamide 4 and an allyl thiolate 5.
(1) (a) Lancaster, J. R. Nitric Oxide. 2008, 19, 68. (b) Zhang, Y.; Hogg,
N. Free Radic. Biol. Med. 2005, 38, 831. (c) Hess, D. T.; Matsumoto, A.;
Kim, S. O.; Marshall, H. E.; Stamler, J. S. Nat. ReV. Mol. Cell. Biol. 2005,
6, 150. (d) Foster, M. W.; McMahon, T. J.; Stamler, J. S. Trends Mol.
Med. 2003, 9, 160.
(2) (a) For a recent RSNO detection method, see: Bechtold, E.; Reisz,
J. A.; Klomsiri, C.; Tsang, A. W.; Wright, M. W.; Poole, L. B.; Furdui,
C. M.; King, S. B. ACS Chem. Biol. 2010, 5, 405. For selected reviews on
RSNO detection, see: (b) Gow, A.; Doctor, A.; Mannick, J.; Gaston, B.
J. Chromatogr., B 2007, 851, 140. (c) Kettenhofen, N. J.; Broniowska, K. A.;
Keszler, A.; Zhang, Y.; Hogg, N. J. Chromatogr., B 2007, 851, 152. (d)
MacArthur, P. H.; Shiva, S.; Gladwin, M. T. J. Chromatogr., B 2007, 851,
93. (e) Jaffrey, S. R. Methods Enzymol. 2005, 396, 105. For deficiencies of
current methods, see: (f) Giustarini, D.; Milzani, A.; Dalle-Donne, I.; Rossi,
J. Chromatogr., B 2007, 851, 124. (g) Gladwin, M. T.; Wang, X.; Hogg,
N. Free Radical Biol. Med. 2006, 41, 557.
(3) (a) Wang, H.; Xian, M. Angew Chem. Int. Ed. 2008, 47, 6598. (b)
Wang, H.; Zhang, J.; Xian, M. J. Am. Chem. Soc. 2009, 131, 13238. (c)
Zhang, J.; Wang, H.; Xian, M. Org. Lett. 2009, 11, 477. (d) Zhang, J.;
Wang, H.; Xian, M. J. Am. Chem. Soc. 2009, 131, 3854. (e) Zhang, J.; Li,
S.; Zhang, D.; Wang, H.; Whorton, A. R.; Xian, M. Org. Lett. 2010, 12,
4208.
(4) (a) Crich, D.; Brebion, F.; Krishnamurthy, V. Org. Lett. 2006, 8,
3593. (b) Crich, D.; Krishnamurthy, V.; Brebion, F.; Karatholuvhu, M.;
Subramanian, V.; Hutton, T. K. J. Am. Chem. Soc. 2007, 129, 10282.
10.1021/ol102491n 2010 American Chemical Society
Published on Web 11/16/2010