10.1002/anie.201801058
Angewandte Chemie International Edition
COMMUNICATION
A. Citta, A. Folda, A. Bindoli, P. Pigeon, S. Top, A. Vessieres, M.
Salmain, G. Jaouen, M. P. Rigobello, J Med Chem 2014, 57, 8849-
8859; o) C. Schmidt, B. Karge, R. Misgeld, A. Prokop, R. Franke, M.
Bronstrup, I. Ott, Chemistry Eur J 2017, 23, 1869-1880; p) T. V.
Serebryanskaya, A. S. Lyakhov, L. S. Ivashkevich, J. Schur, C. Frias, A.
Prokop, I. Ott, Dalton Trans 2015, 44, 1161-1169; q) W. J. Yan, Q.
Wang, C. H. Yuan, F. Wang, Y. Ji, F. Dai, X. L. Jin, B. Zhou, Free
Radic Biol Med 2016, 97, 109-123.
In conclusion, conjugation of the 1, 2-dithiolane moiety with the
anticancer drug gemcitabine via a carbamate linker generates
the prodrug S-Gem, which is specifically activated by TrxRs to
liberate the parent drug gemcitabine. S-Gem shows less
cytotoxicity compared to gemcitabine, but exhibits TrxR-
dependent cytotoxicity. Thus, S-Gem deserves further
[4]
a) E. S. J. Arner, Adv Cancer Res 2017, 136, 139-151; b) D. F.
Mahmood, A. Abderrazak, K. El Hadri, T. Simmet, M. Rouis, Antioxid
Redox Signal 2013, 19, 1266-1303; c) W. Cai, L. Zhang, Y. Song, B.
Wang, B. Zhang, X. Cui, G. Hu, Y. Liu, J. Wu, J. Fang, Free Radic Biol
Med 2012, 52, 257-265.
development as
a
chemotherapeutic agent for TrxR-
overexpressing cancer cells. In addition, as a proof of concept,
the discovery of S-Gem also provides a novel strategy for
targeting TrxR enzymes in cancer cells.
[5]
[6]
[7]
a) H. Ma, J. Zhang, Z. Zhang, Y. Liu, J. Fang, Chem Commun 2016, 52,
12060-12063; b) Y. Liu, H. Ma, L. Zhang, Y. Cui, X. Liu, J. Fang, Chem
Commun 2016, 52, 2296-2299; c) L. Zhang, D. Duan, Y. Liu, C. Ge, X.
Cui, J. Sun, J. Fang, J Am Chem Soc 2014, 136, 226-233.
Experimental Section
a) E. S. J. Arner, Methods Mol Biol 2018, 1661, 301-309; b) R.
Engelman, T. Ziv, E. S. J. Arner, M. Benhar, Free Radic Biol Med 2016,
97, 375-385; c) S. Peng, B. Zhang, J. Yao, D. Duan, J. Fang, Food
Funct 2015, 6, 2091-2100.
Experimental Details were described in the Supporting Information.
a) R. Walther, J. Rautio, A. N. Zelikin, Adv Drug Deliv Rev 2017, 118,
65-77; b) M. H. Lee, A. Sharma, M. J. Chang, J. Lee, S. Son, J. L.
Sessler, C. Kang, J. S. Kim, Chem Soc Rev 2018, 47, 28-52; c) M. H.
Lee, J. L. Sessler, J. S. Kim, Acc Chem Res 2015, 48, 2935-2946; d) M.
H. Lee, E. J. Kim, H. Lee, H. M. Kim, M. J. Chang, S. Y. Park, K. S.
Hong, J. S. Kim, J. L. Sessler, J Am Chem Soc 2016, 138, 16380-
16387; e) E. J. Kim, S. Bhuniya, H. Lee, H. M. Kim, C. Cheong, S. Maiti,
K. S. Hong, J. S. Kim, J Am Chem Soc 2014, 136, 13888-13894; f) X.
Wu, X. Sun, Z. Guo, J. Tang, Y. Shen, T. D. James, H. Tian, W. Zhu, J
Am Chem Soc 2014, 136, 3579-3588; g) Z. Yang, J. H. Lee, H. M. Jeon,
J. H. Han, N. Park, Y. He, H. Lee, K. S. Hong, C. Kang, J. S. Kim, J Am
Chem Soc 2013, 135, 11657-11662; h) L. R. Staben, S. G. Koenig, S.
M. Lehar, R. Vandlen, D. Zhang, J. Chuh, S. F. Yu, C. Ng, J. Guo, Y.
Liu, A. Fourie-O'Donohue, M. Go, X. Linghu, N. L. Segraves, T. Wang,
J. Chen, B. Wei, G. D. Phillips, K. Xu, K. R. Kozak, S. Mariathasan, J. A.
Flygare, T. H. Pillow, Nat Chem 2016, 8, 1112-1119; i) Y. Ota, Y. Itoh,
A. Kaise, K. Ohta, Y. Endo, M. Masuda, Y. Sowa, T. Sakai, T. Suzuki,
Angew Chem Int Ed 2016, 55, 16115-16118; j) B. Renoux, F. Raes, T.
Legigan, E. Peraudeau, B. Eddhif, P. Poinot, I. Tranoy-Opalinski, J.
Alsarraf, O. Koniev, S. Kolodych, S. Lerondel, A. Le Pape, J. Clarhaut,
S. Papot, Chem Sci 2017, 8, 3427-3433.
Acknowledgements
The financial supports from the National Natural Science
Foundation of China (21572093
University (the Fundamental Research Funds for the Central
Universities, lzujbky-2017-ot02 & lzujbky-2017-sp06) and the
111 project are greatly acknowledged.
& 21778028), Lanzhou
Keywords: Thioredoxin reductase • Prodrug • 1, 2-Dithiolane •
Redox regulation• Cancer
Conflict of interest
The authors declare no conflict of interest.
[1]
[2]
[3]
a) J. Zhang, X. Li, X. Han, R. Liu, J. Fang, Trends Pharmacol Sci 2017,
38, 794-808; b) A. Matsuzawa, Arch Biochem Biophys 2017, 617, 101-
105; c) M. Dagnell, E. E. Schmidt, E. S. J. Arner, Free Radic Biol Med
2018, 115, 484-496.
a) B. Zhang, C. Ge, J. Yao, Y. Liu, H. Xie, J. Fang, J Am Chem Soc
2015, 137, 757-769; b) L. Zhong, A. Holmgren, J Biol Chem 2000, 275,
18121-18128; c) J. Lu, A. Holmgren, J Biol Chem 2009, 284, 723-727;
d) E. S. Arner, Exp Cell Res 2010, 316, 1296-1303.
[8]
[9]
a) L. de Sousa Cavalcante, G. Monteiro, Eur J Pharmacol 2014, 741, 8-
16; b) E. Mini, S. Nobili, B. Caciagli, I. Landini, T. Mazzei, Ann Oncol
2006, 17 Suppl 5, v7-12.
a) H. Han, W. Teng, T. Chen, J. Zhao, Q. Jin, Z. Qin, J. Ji, Chem
Commun 2017, 53, 9214-9217; b) N. Cox, J. R. Kintzing, M. Smith, G.
A. Grant, J. R. Cochran, Angew Chem Int Ed 2016, 55, 9894-9897; c) J.
T. Weiss, J. C. Dawson, C. Fraser, W. Rybski, C. Torres-Sanchez, M.
Bradley, E. E. Patton, N. O. Carragher, A. Unciti-Broceta, J Med Chem
2014, 57, 5395-5404; d) S. Hazra, S. Ort, M. Konrad, A. Lavie,
Biochem 2010, 49, 6784-6790.
a) E. S. Arner, M. Bjornstedt, A. Holmgren, J Biol Chem 1995, 270,
3479-3482; b) J. Zhang, J. Yao, S. Peng, X. Li, J. Fang, Biochim
Biophys Acta 2017, 1863, 129-138; c) L. Xie, Z. Luo, Z. Zhao, T. Chen,
J Med Chem 2017, 60, 202-214; d) H. L. Ng, X. Ma, E. H. Chew, W. K.
Chui, J Med Chem 2017, 60, 1734-1745; e) J. Zhang, Y. Li, D. Duan, J.
Yao, K. Gao, J. Fang, Biochem Pharmacol 2016, 102, 34-44; f) D.
Duan, J. Zhang, J. Yao, Y. Liu, J. Fang, J Biol Chem 2016, 291, 10021-
10031; g) B. Zhang, D. Duan, C. Ge, J. Yao, Y. Liu, X. Li, J. Fang, J
Med Chem 2015, 58, 1795-1805; h) M. Soethoudt, A. V. Peskin, N.
Dickerhof, L. N. Paton, P. E. Pace, C. C. Winterbourn, Free Radic Biol
Med 2014, 77, 331-339; i) Y. Liu, D. Duan, J. Yao, B. Zhang, S. Peng,
H. Ma, Y. Song, J. Fang, J Med Chem 2014, 57, 5203-5211; j) L.
Huang, Y. Chen, B. Liang, B. Xing, G. Wen, S. Wang, X. Yue, C. Zhu, J.
Du, X. Bu, Chem Commun 2014, 50, 6987-6990; k) F. F. Gan, K. K.
Kaminska, H. Yang, C. Y. Liew, P. C. Leow, C. L. So, L. N. Tu, A. Roy,
C. W. Yap, T. S. Kang, W. K. Chui, E. H. Chew, Antioxid Redox Signal
2013, 19, 1149-1165; l) O. Karaca, V. Scalcon, S. M. Meier-Menches,
R. Bonsignore, J. Brouwer, F. Tonolo, A. Folda, M. P. Rigobello, F. E.
Kuhn, A. Casini, Inorg Chem 2017, 56, 14237-14250; m) V. Scalcon, M.
Salmain, A. Folda, S. Top, P. Pigeon, H. Z. Shirley Lee, G. Jaouen, A.
Bindoli, A. Vessieres, M. P. Rigobello, Metallomics 2017, 9, 949-959; n)
[10] a) S. Bhuniya, S. Maiti, E. J. Kim, H. Lee, J. L. Sessler, K. S. Hong, J. S.
Kim, Angew Chem Int Ed 2014, 53, 4469-4474; b) S. Maiti, N. Park, J.
H. Han, H. M. Jeon, J. H. Lee, S. Bhuniya, C. Kang, J. S. Kim, J Am
Chem Soc 2013, 135, 4567-4572; c) M. H. Lee, J. Y. Kim, J. H. Han, S.
Bhuniya, J. L. Sessler, C. Kang, J. S. Kim, J Am Chem Soc 2012, 134,
12668-12674; d) F. Kong, Y. Zhao, Z. Liang, X. Liu, X. Pan, D. Luan, K.
Xu, B. Tang, Anal Chem 2017, 89, 688-693.
This article is protected by copyright. All rights reserved.