Citation: Ge Weiwei, Chen Jing, Zhang Ye, Zong Liang, Zhang Ming, Dong Junjun. Semiregioselective Formation of Linaclotide with Orthogonal Cysteine Protection Strategy[J]. Chinese Journal of Organic Chemistry, ;2017, 37(9): 2409-2415. doi: 10.6023/cjoc201704020 shu

Semiregioselective Formation of Linaclotide with Orthogonal Cysteine Protection Strategy

Ge Weiwei ^a,b ,
Chen Jing ^a ,
Zhang Ye ^a ,
Zong Liang ^a ,
Zhang Ming ^a ,
Dong Junjun ^a,,

a.
Department of Bio-Chem Defence, Institute of Nuclear, Biological and Chemical Defence, Beijing 102205
b.
Department of Training, Public Security Fire Forces College, Kunming 650208

Corresponding author: Dong Junjun, dqshi@suda.edu.cn
Received Date: 12 April 2017
Revised Date: 15 May 2017
Available Online: 24 September 2017
Fund Project: the State Key Laboratory of Nuclear, Biological and Chemical Protection for Civilian SKLNBC2013-01KProject supported by the State Key Laboratory of Toxicology and Medical Countermeasures of China (No. PMC201507) and the State Key Laboratory of Nuclear, Biological and Chemical Protection for Civilian (No. SKLNBC2013-01K)the State Key Laboratory of Toxicology and Medical Countermeasures of China PMC201507

Figures(8)

Six linear precursors of linaclotide containing different protected cysteine residues were synthesized by Fmoc solid-phase methods. Wang resin was used in the peptide syntheses. The protective groups of cysteine thiol were trityl (Trt) and acetamidomethyl (Acm) in the different positions. The six linear precursors of linaclotide include three[4 Trt+2 Acm] and three[2 Trt+4 Acm] ones. The linaclotide with three disulfide bonds was prepared from these linear precursors by semiregioselective strategy. Firstly, linear peptides were cleaved from Wang resins by TFA-TIS-H₂O. At the same time, the Trt groups were removed to give free thiol groups, whereas Acm groups were still remained in the peptides. Secondly, the free thiol groups were oxidized by 20% hemin/DIEA system to from disulfide bond(s). Finally, cysteines containing Acm groups were deprotected by CH₃SiCl₃/PhS(O)Ph/TFA coaktail and disulfide bond(s) were formed simultaneously. The precursors of peptides[4 Trt(2, 5, 10, 13)+2 Acm(1, 6)], [2 Trt(1, 6)+4 Acm(2, 5, 10, 13)] and[2 Trt(5, 13)+2 Acm(1, 2, 6, 10)] give linaclotide at the conversion ratios of 71.9%, 31.5%, and 81.4% respectively. Other three peptides failed in the conversion or were found to be less suitable to prepare linaclotide. Our results indicated that the order of disulfide bond formation is very important to prepare linaclotide by using semiregioselective or regioselective strategies. The Cys5-Cys13 disulfide bond is the most privileged and should be formed firstly among the three disulfide bonds in linaclotide.
- linaclotide,
- disulfide,
- oxidation,
- semiregioselective
1. [1]
  Cambridge, M. A. US 7304036, 2007.
2. [2]
  Harris, L. A.; Crowell, D. Curr. Opin. Mol. Ther. 2007, 9, 403.
3. [3]
  Andresen, V.; Camilleri, M. Drugs Future 2008, 33, 570. doi: 10.1358/dof.2008.033.07.1214164
4. [4]
  Wu Q. L.; Liu Z. G.; Fu C.; Lin Y. B.; Dai Q. Y. Chin. J. Org. Chem. 2010, 30, 1517(in Chinese).
5. [5]
  Eliasen, R.; Andresen, T. L.; Conde-Frieboes, K. W. Peptides 2012, 34, 144.
6. [6]
  Dekan, Z.; Mobli, M.; Pennington, M. W.; Fung, E.; Nemeth, E.; Alewood, P. F. Angew. Chem., Int. Ed. 2014, 53, 1. doi: 10.1002/anie.v53.1
7. [7]
  Veber, D. F.; Milkowski, J. D.; Varga, S. L.; Denkewalter, R. G.; Hirschmann, R. J. Am. Chem. Soc. 1972, 94, 5456. doi: 10.1021/ja00770a600
8. [8]
  Munson, M. C.; Barany, G. J. Am. Chem. Soc. 1993, 115, 10203. doi: 10.1021/ja00075a040
9. [9]
  Kawakami, T.; Aimoto, S. Tetrahedron Lett. 1998, 39, 7901. doi: 10.1016/S0040-4039(98)01752-3
10. [10]
  Hunter, M. J.; Komives, E. A. Anal. Biochem. 1995, 228, 173. doi: 10.1006/abio.1995.1333
11. [11]
  Miriam, G. B.; Judit, T. P.; Marta, P. B.; Marta, P. B.; Oleg, W.; Matthieu, G.; Fernando, A. Biopolymers 2011, 96, 69. doi: 10.1002/bip.v96.1
12. [12]
  Ge, W. W.; Chen, J.; Zong, L.; Li, J.; Sui, S. H.; Wu, W. H.; Zhang, M.; Dong, J. J. Chem. J. Chin. Univ. 2017, 38, 1052(in Chinese). doi: 10.7503/cjcu20160940
13. [13]
  Akaji, K.; Tatsumi, T.; Yoshida, M.; Kimura, T.; Fujiwara, Y.; Kiso, Y. J. Am. Chem. Soc. 1992, 114, 4137. doi: 10.1021/ja00037a015
14. [14]
  Ildikó, S.; Gitta, S.; Ference, H.; Gábor, M. Biopolymers 2006, 88, 20.
15. [15]
  Ge, W. W.; Chen, J.; Zhang, Y.; Zong, L.; Zhang, M.; Dong, J. J. J. Int. Pharm. Res. 2017, 44, 585(in Chinese).
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