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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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.
KeywordsHistidine Microwave-assisted synthesis Nanoparticles Racemization Solid-phase peptide synthesis Synthesis in water
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.
The manuscript does not contain clinical studies or patient data.
- Anastas PT, Warner JC (1998) Green chemistry: theory and practice. Oxford University Press, New YorkGoogle Scholar
- Angeletti RH, Bibbs L, Bonewald LF, Fields GB, Kelly JW, McMurray JS, Moore WT, Weintraub ST (1997) Analysis of racemization during “standard” solid phase peptide synthesis: a multicenter study. In: Marshak DR (ed) Techniques in protein chemistry III. Academic Press Inc, San Diego, pp 875–890Google Scholar
- Bodanszky M, Bodanszky A (1967) Racemization in peptide chemistry. Mechanism-specific models. Chem Commun 1967:591–592Google Scholar
- Collins JM, Collin MJ (2003) Novel method for enhanced solid-phase peptide synthesis using microwave energy. Biopolymers 71:361–366Google Scholar
- Erdélyi M, Gogoll A (2002) Rapid microwave-assisted solid-phase peptide synthesis. Synthesis 11:1592–1596Google Scholar
- Hojo K, Maeda M, Kawasaki K (2004a) A water-soluble N-protecting group, 2-[phenyl(methyl)sulfonio]ethoxycarbonyl tetrafluoroborate, and its application to peptide synthesis. Tetrahedron 60:1875–1866Google Scholar
- Kaminski ZJ, Paneth P, Rudzinski JA (1998) Study on the activation of carboxylic acids by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine and 2-chloro-4,6-diphenoxy-1.3.5-triazine. J Org Chem 63:4248–4225Google Scholar
- Robertson N, Jiang L, Ramage R (1999) Racemisation studies of a novel reagent for solid-phase peptide synthesis. Tetrahedron 54:14233–14254Google Scholar
- Veber DF (1975) Peptide synthesis from the practitioner’s point of view. In: Walter R, Meienhofer J (eds) Peptides: chemistry, structure and biology. Ann Arbor Science Publishers, Michigan, pp 307–316Google Scholar