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A convenient preparation of N ε-methyl-l-lysine derivatives and its application to the synthesis of histone tail peptides

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Abstract

A convenient route is established for the preparation of N α-Fmoc-N ε-(Boc, methyl)-l-lysine and N α-Fmoc-N ε-dimethyl-l-lysine as building blocks to be used for the synthesis of methylated peptides. This methodology is based on the use of malonate derivatives and dibromobutane to produce key intermediates, l-2-amino-6-bromohexanoic acid derivatives, which could be modified to the required group at the ε-position. Fmoc-protection is accessible, so these compounds can be used in solution as well as in solid-phase peptide synthesis. Also the peptides containing these methylated lysines have been proved to resist the action of trypsin and lysyl endopeptidase. Thus, this new method could be considered as an improvement of the synthesis of N ε-methyl-l-lysine derivatives.

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Fig. 1
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Abbreviations

AcOH:

Acetic acid

AMC:

7-Amino-4-methylcoumarin

Boc:

tert-Butyloxycarbonyl

DCC:

Dicyclohexylcarbodiimide

DCM:

Dichloromethane

DIEA:

N,N-Diisopropylethylamine

DMAP:

4-Dimethylaminopyridine

DMF:

N,N-Dimethylformamide

Fmoc:

9-Fluorenylmethyloxycarbonyl

Fmoc-OSu:

N-(9-Fluorenylmethoxycarbonyloxy)succinimide

HBTU:

O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

HOBt·H2O:

1-Hydroxybenzotriazole hydrate

HPLC:

High-performance liquid chromatography

HRMS (FAB):

High-resolution fast atom bombardment mass spectrometry

LCMS:

Liquid chromatography mass spectrometry

MCA:

4-Methylcoumaryl-7-amide

TFA:

Trifluoroacetic acid

TLC:

Thin layer chromatography

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Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu, Kitakyushu, 808-0196, Japan

    Hongfang Chi, Md. Shahidul Islam, Tienabe K. Nsiama, Tamaki Kato & Norikazu Nishino

Authors
  1. Hongfang Chi
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  2. Md. Shahidul Islam
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  3. Tienabe K. Nsiama
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  4. Tamaki Kato
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  5. Norikazu Nishino
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Corresponding author

Correspondence to Tamaki Kato.

Electronic supplementary material

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726_2014_1690_MOESM1_ESM.doc

Supplementary material 1 (DOC 9275 kb) Supplementary data (HPLC profiles and MS data of amino acid derivatives and synthetic peptides) associated with this article can be found, in the online version

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Chi, H., Islam, M.S., Nsiama, T.K. et al. A convenient preparation of N ε-methyl-l-lysine derivatives and its application to the synthesis of histone tail peptides. Amino Acids 46, 1305–1311 (2014). https://doi.org/10.1007/s00726-014-1690-6

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  • DOI: https://doi.org/10.1007/s00726-014-1690-6

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