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Amino Acids

, Volume 46, Issue 10, pp 2347–2354 | Cite as

Aqueous microwave-assisted solid-phase peptide synthesis using Fmoc strategy. III: Racemization studies and water-based synthesis of histidine-containing peptides

  • Keiko HojoEmail author
  • Natsuki Shinozaki
  • Koushi Hidaka
  • Yuko Tsuda
  • Yoshinobu Fukumori
  • Hideki Ichikawa
  • John D. WadeEmail author
Original Article

Abstract

In this study, we describe the first aqueous microwave-assisted synthesis of histidine-containing peptides in high purity and with low racemization. We have previously shown the effectiveness of our synthesis methodology for peptides including difficult sequences using water-dispersible 9-fluorenylmethoxycarbonyl-amino acid nanoparticles. It is an organic solvent-free, environmentally friendly method for chemical peptide synthesis. Here, we studied the racemization of histidine during an aqueous-based coupling reaction with microwave irradiation. Under our microwave-assisted protocol using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, the coupling reaction can be efficiently performed with low levels of racemization of histidine. Application of this water-based microwave-assisted protocol with water-dispersible 9-fluorenylmethoxycarbonyl-amino acid nanoparticles led to the successful synthesis of the histidine-containing hexapeptide neuropeptide W-30 (10–15), Tyr-His-Thr-Val-Gly-Arg-NH2, in high yield and with greatly reduced histidine racemization.

Keywords

Histidine Microwave-assisted synthesis Nanoparticles Racemization Solid-phase peptide synthesis Synthesis in water 

Notes

Acknowledgments

We are grateful to Dr. Hajime Hibino and Prof. Yuji Nishiuchi (Peptide Institute, Japan) for valuable advice and providing Fmoc-His(MBom)-OH. This work supported by a “Strategic Research Foundation” at Private Universities matching fund subsidy from the Japanese Ministry of Education, Culture, Sports Science and Technology, 2012–2016 (S1201010) and “Takeda Science Foundation”. Studies at the Florey Institute of Neuroscience and Mental Health were supported by the Victorian Government Operational Infrastructure Support Program.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

The manuscript does not contain clinical studies or patient data.

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Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Keiko Hojo
    • 1
    • 2
    Email author
  • Natsuki Shinozaki
    • 1
  • Koushi Hidaka
    • 1
  • Yuko Tsuda
    • 1
  • Yoshinobu Fukumori
    • 1
  • Hideki Ichikawa
    • 1
  • John D. Wade
    • 2
    • 3
    Email author
  1. 1.Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life SciencesKobe Gakuin UniversityKobeJapan
  2. 2.The Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneMelbourneAustralia
  3. 3.School of ChemistryUniversity of MelbourneMelbourneAustralia

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