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

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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.

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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.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences and Cooperative Research Center of Life Sciences, Kobe Gakuin University, Chuo-ku, Kobe, 650-8586, Japan

    Keiko Hojo, Natsuki Shinozaki, Koushi Hidaka, Yuko Tsuda, Yoshinobu Fukumori & Hideki Ichikawa

  2. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, 3010, Australia

    Keiko Hojo & John D. Wade

  3. School of Chemistry, University of Melbourne, Melbourne, VIC, 3010, Australia

    John D. Wade

Authors
  1. Keiko Hojo
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  2. Natsuki Shinozaki
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  3. Koushi Hidaka
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  4. Yuko Tsuda
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  5. Yoshinobu Fukumori
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  6. Hideki Ichikawa
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  7. John D. Wade
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Correspondence to Keiko Hojo or John D. Wade.

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Hojo, K., Shinozaki, N., Hidaka, K. et al. Aqueous microwave-assisted solid-phase peptide synthesis using Fmoc strategy. III: Racemization studies and water-based synthesis of histidine-containing peptides. Amino Acids 46, 2347–2354 (2014). https://doi.org/10.1007/s00726-014-1779-y

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  • DOI: https://doi.org/10.1007/s00726-014-1779-y

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