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Ibaraki, Japan

Hibino H.,Peptide Institute Inc. | Miki Y.,Kinki University | Nishiuchi Y.,Peptide Institute Inc. | Nishiuchi Y.,Osaka University
Journal of Peptide Science | Year: 2012

The 4-methoxybenzyloxymethyl (MBom) group was introduced at the Nπ-position of the histidine (His) residue by using a regioselective procedure, and its utility was examined under standard conditions used for the conventional and the microwave (MW)-assisted solid phase peptide synthesis (SPPS) with 9-fluorenylmethyoxycarbonyl (Fmoc) chemistry. The Nπ-MBom group fulfilling the requirements for the Fmoc strategy was found to prevent side-chain-induced racemization during incorporation of the His residue even in the case of MW-assisted SPPS performed at a high temperature. In particular, the MBom group proved to be a suitable protecting group for the convergent synthesis because it remains attached to the imidazole ring during detachment of the protected His-containing peptide segments from acid-sensitive linkers by treatment with a weak acid such as 1% trifluoroacetic acid in dichloromethane. We also demonstrated the facile synthesis of Fmoc-His(π-MBom)-OH with the aid of purification procedure by crystallization to effectively remove the undesired τ-isomer without resorting to silica gel column chromatography. This means that the present synthetic procedure can be used for large-scale production without any obstacles. © 2012 European Peptide Society and John Wiley & Sons, Ltd. Source


Taichi M.,Peptide Institute Inc. | Yamazaki T.,Japan National Institute of Agrobiological Science | Nishiuchi Y.,Peptide Institute Inc. | Nishiuchi Y.,Osaka University
ChemBioChem | Year: 2012

Rational design of inhibitors: The cis-amide backbone at position 7 in the serine protease inhibitor marinostatin was replaced with an E or Z olefin. The E olefin analogue was not active, but the Z analogue was. The cis conformation might play a critical role in organizing a canonical structure for binding to proteases. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Hibino H.,Peptide Institute Inc. | Nishiuchi Y.,Peptide Institute Inc. | Nishiuchi Y.,Osaka University
Organic Letters | Year: 2012

The 4-methoxybenzyloxymethyl (MBom) group was introduced for sulfhydryl protection of Cys in combination with Fmoc chemistry. The MBom group proved to substantially suppress racemization of Cys during its incorporation mediated by phosphonium or uronium reagents. Furthermore, this group was found to significantly reduce racemization of the C-terminal Cys linked to a hydroxyl resin during repetitive base treatment, in comparison with the usually used trityl (Trt) and acetamidomethyl (Acm) groups. © 2012 American Chemical Society. Source


Mochizuki M.,Peptide Institute Inc. | Hibino H.,Peptide Institute Inc. | Nishiuchi Y.,Peptide Institute Inc. | Nishiuchi Y.,Osaka University
Organic Letters | Year: 2014

Tritylation using trityl alcohol (Trt-OH) in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is a convenient and efficient procedure that can offer S-protection of the Cys located in fully unprotected peptides. The procedure simply requires Trt-OH and HFIP to selectively promote S-tritylation in the presence of peptide nucleophilic functionalities. © 2014 American Chemical Society. Source


Hibino H.,Peptide Institute Inc. | Miki Y.,Kinki University | Nishiuchi Y.,Peptide Institute Inc. | Nishiuchi Y.,Osaka University
Journal of Peptide Science | Year: 2014

Phosphonium and uronium salt-based reagents enable efficient and effective coupling reactions and are indispensable in peptide chemistry, especially in machine-assisted SPPS. However, after the activating and coupling steps with these reagents in the presence of tertiary amines, Fmoc derivatives of Cys are known to be considerably racemized during their incorporation. To avoid this side reaction, a coupling method mediated by phosphonium/uronium reagents with a weaker base, such as 2,4,6-trimethylpyridine, than the ordinarily used DIEA or that by carbodiimide has been recommended. However, these methods are appreciably inferior to the standard protocol applied for SPPS, that is, a 1 min preactivation procedure of coupling with phosphonium or uronium reagents/DIEA in DMF, in terms of coupling efficiency, and also the former method cannot reduce racemization of Cys(Trt) to an acceptable level (<1.0%) even when the preactivation procedure is omitted. Here, the 4,4′-dimethoxydiphenylmethyl and 4-methoxybenzyloxymethyl groups were demonstrated to be acid-labile S-protecting groups that can suppress racemization of Cys to an acceptable level (<1.0%) when the respective Fmoc derivatives are incorporated via the standard SPPS protocol of phosphonium or uronium reagents with the aid of DIEA in DMF. Furthermore, these protecting groups significantly reduced the rate of racemization compared to the Trt group even in the case of microwave-assisted SPPS performed at a high temperature. © 2013 The Authors. European Peptide Society published by John Wiley & Sons, Ltd. Source

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