90% of 9 (5 mM) in about 10 min. Although Na2S also showed
ability to reduce 9, the process was much slower (~30% after 50
min). Next, we tested if in-situ generated H2S2 could reduce 9. To
this end, 2a and 3a were incubated for 30 min and treated with 9.
Since 2a, 3a and 9 were all soluble in organic solvents, these
experiments were done in THF. As shown in Figure 5-c/d, a dose-
dependent decrease of UV absorption at 548 nm was detected,
indicating the reduction of 9, whereas 2a and 3a alone could not
reduce 9. Interestingly, in-situ generated H2S by 7 and TBAF could
not reduce 9 under this condition. These results suggest that H2S2
is much more potent than H2S in reducing tetrazines. This finding
may be used to develop tetrazine-based H2Sn sensors.
9.
Cortese-Krott, M. M.; Kuhnle, G. G. C.; Dyson, A.;
Fernandez, B. O.; Grman, M.; DuMond, J. F.; Barrow,
M. P.; McLeod, G.; Nakagawa, H.; Ondrias, K.; Nagy,
P.; King, S. B.; Saavedra, J. E.; Keefer, L. K.; Kelm, M.;
Butler, A. R.; Feelisch, M. Proc. Natl. Acad. Sci. USA.
2015, 112, 4651.
Miyamoto, R.; Koike, S.; Takano, Y.; Shibuya, N.;
Kimura, Y.; Hanaoka, K.; Urano, Y.; Ogasawara, Y.;
Kimura, H. Sci. Rep. 2017, 7, 45995.
Olson, K. R.; Gao, Y.; Arif, F.; Arora, K.; Patel, S.;
DeLeon, E. R.; Sutton, T. R.; Feelisch, M.; Cortese-
Krott, M. M.; Straub, K. D. Redox Biol. 2018, 15, 74.
Kimura, Y.; Mikami, Y.; Osumi, K.; Tsugane, M.; Oka,
J.-i.; Kimura, H. FASEB J. 2013, 27, 2451.
10.
11.
12.
13.
14
Koike, S.; Ogasawara, Y.; Shibuya, N.; Kimura, H.;
Ishii, K. FEBS Lett. 2013, 587, 3548.
Brown, A.; Battles, J. Synth. React. Inorg. Met-Org.
Chem. 1984, 14, 945.
15.
Kang, J.; Xu, S.; Radford, M. N.; Zhang, W.; Kelly, S.
S.; Day, J. J.; Xian, M. Angew. Chem. Int. Ed. 2018, 57,
5893.
16.
17.
Yu, B.; Zheng, Y.; Yuan, Z.; Li, S.; Zhu, H.; De La Cruz,
L. K.; Zhang, J.; Ji, K.; Wang, S.; Wang, B. J. Am. Chem.
Soc. 2018, 140, 30.
Roger, T.; Raynaud, F.; Bouillaud, F.; Ransy, C.;
Simonet, S.; Crespo, C.; Bourguignon, M.-P.;
Villeneuve, N.; Vilaine, J.-P.; Artaud, I.; Galardon, E.
ChemBioChem 2013, 14, 2268.
18.
19.
Mali, S. M.; Gopi, H. N. J. Org. Chem. 2014, 79, 2377.
Liu, C.; Chen, W.; Shi, W.; Peng, B.; Zhao, Y.; Ma, H.;
Xian, M. J. Am. Chem. Soc. 2014, 136, 7257.
Peng, B.; Chen, W.; Liu, C.; Rosser, E. W.; Pacheco, A.;
Aguilar, H. C.; Xian, M. Chem. Eur. J. 2014, 20, 1010.
Bibli, S.-I.; Luck, B.; Zukunft, S.; Wittig, J.; Chen, W.;
Xian, M.; Papapetropoulos, A.; Hu, J.; Fleming, I.;
Redox Biol. 2018, 18, 295.
20.
21.
Figure 5 a) Reduction of tetrazine. b) Time-dependent reduction of 9
(5 mM) by Na2S or Na2S2 (25 mM) in THF w/ 20% water. c) Dose-
dependent reduction of 9 (1 mM) by H2S2 generated from 2a and 3a
in THF. d) Reduction of 9 (1 mM) by various species (4 mM) in THF.
In summary, we demonstrated here that diacyl disulfides could
be used as precursors to produce H2S2 in both aqueous buffers and
organic solvents. H2S2 generated by this method could potently
reduce DPPH and tetrazines. These results will aid future
understanding of H2Sn.
22.
Kimura, Y.; Koike, S.; Shibuya, N.; Lefer, D.;
Ogasawara, Y.; Kimura, H. Sci. Rep. 2017, 7, 10459.
Riggs, A. J. Biol. Chem. 1961, 236, 6.
Smyth, D. G.; Nagamatsu, A.; Fruton, J. S. J. Am. Chem.
Soc. 1960, 82, 4600.
23.
24.
25.
Ida, T.; Sawa, T.; Ihara, H.; Tsuchiya, Y.; Watanabe, Y.;
Kumagai, Y.; Suematsu, M.; Motohashi, H.; Fujii, S.;
Matsunaga, T.; Yamamoto, M.; Ono, K.; Devarie-Baez,
N. O.; Xian, M.; Fukuto, J. M.; Akaike, T. Proc. Natl.
Acad. Sci. USA. 2014, 111, 7606.
Acknowledgments
This work was supported by the National Institute of Health
(R01GM125968).
26.
Filipovic, M. R.; Zivanovic, J.; Alvarez, B.; Banerjee,
R. Chem. Rev. 2018, 118, 1253.
References
27.
28.
Blois, M. S. Nature 1958, 181, 1199.
Blackman, M. L.; Royzen, M.; Fox, J. M.; J. Am. Chem.
Soc. 2008, 130, 13518.
Steiger, A. K.; Yang, Y.; Royzen, M.; Pluth, M. D.
Chem. Commun. 2017, 53, 1378.
Zhao, Z.; Cao, L.; Zhang, T.; Hu, R.; Wang, S.; Li, S.;
Li, Y.; Yang, G. ChemistrySelect 2016, 1, 2581.
1.
2.
Szabó, C. Nat. Rev. Drug Discov. 2007, 6, 917.
Wallace, J. L.; Wang, R. Nat. Rev. Drug Discov. 2015,
14, 329.
Wang, R. Physio. Rev. 2012, 92, 791.
Li, L.; Rose, P.; Moore, P. K. Annu. Rev. Pharmacol.
2011, 51, 169.
29.
30.
3.
4.
5.
6.
7.
WANG, R. FASEB J. 2002, 16, 1792.
Kimura, H. Proc. Jpn. Acad. B-Phys. 2015, 91, 131.
Akaike, T.; Ida, T.; Wei,; Nishida, M.; Kumagai, Y.;
Alam, M. M.; Ihara, H.; Sawa, T.; Matsunaga, T.;
Kasamatsu, S.; Nishimura, A.; Morita, M.; Tomizawa,
K.; Nishimura, A.; Watanabe, S.; Inaba, K.; Shima, H.;
Tanuma, N.; Jung, M.; Fujii, S.; Watanabe, Y.;
Ohmuraya, M.; Nagy, P.; Feelisch, M.; Fukuto, J. M.;
Motohashi, H. Nat. Comm. 2017, 8, 1177.
Liu, H.; Radford, M. N.; Yang, C.-T.; Chen, W.; Xian,
M. Br. J. Pharmaco. 2019, 176, 616.
8.