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Amino Acids

, Volume 44, Issue 2, pp 321–333 | Cite as

Direct access to side chain N,N′-diaminoalkylated derivatives of basic amino acids suitable for solid-phase peptide synthesis

  • Jean-Philippe Pitteloud
  • Nina Bionda
  • Predrag CudicEmail author
Original Article

Abstract

A simple and efficient one-pot procedure that enables rapid access to orthogonally protected N,N′-diaminoalkylated basic amino acid building blocks fully compatible with standard Boc and Fmoc solid-phase peptide synthesis is reported. Described synthetic approach includes double reductive alkylation of N α-protected diamino acids with N-protected amino aldehydes in the presence of sodium cyanoborohydride. This approach allows preparation of symmetrical, as well as unsymmetrical, basic amino acid derivatives with branched side-chains that can be further modified, enhancing their synthetic utility. The suitability of the synthesized branched basic amino acid building blocks for use in standard solid-phase peptide synthesis has been demonstrated by synthesis of an indolicidin analogue in which the lysine residue was substituted with the synthetic derivative N α -(9H-fluorenyl-9-methoxycarbonyl)-N β ,N β -bis[2-(tert-butoxycarbonylamino)ethyl]-l-2,3-diaminopropionic acid. This substitution resulted in an analogue with more ordered secondary structure in 2,2,2-trifluoroethanol and enhanced antibacterial activity without altering hemolytic activity.

Graphical abstract

Keywords

N-alkylation Reductive amination One-pot procedure Branched basic amino acids Solid-phase peptide synthesis Indolicidin 

Abbreviations

AcOH

Acetic acid

ACN

Acetonitrile

Aloc

Allyloxycarbonyl

Boc

Tert-butoxycarbonyl

CAMP

Cationic antimicrobial peptide

Cbz

Benzyloxycarbonyl

CD

Circular dichroism

CPP

Cell-penetrating peptide

DCM

Dichloromethane

EDT

1,2-Ethanedithiol

EtOAc

Ethyl acetate

Fmoc

9-Fluorenylmethoxycarbonyl

FA

Formic acid

HPLC

High-performance liquid chromatography

LPS

Lypopolysaccharide

MALDI-TOF MS

Matrix-assisted laser desorption ionization time of flight mass spectrometry

MAP

Multiantigen peptide system

MBHA

4-Methylbenzhydrylamine

MeOH

Methanol

MIC

Minimal inhibitory concentration

Mtt

4-Methoxytrityl

NMR

Nuclear magnetic resonance

PBS

Phosphate buffered saline

SPPS

Solid-phase peptide synthesis

TFA

Trifluoroacetic acid

TFE

2,2,2-Trifluoroethanol

TIS

Triisopropylsilane

TLC

Thin-layer chromatography

tR

Retention time

Trt

Trityl

Notes

Acknowledgments

We acknowledge support of the N,N′-diaminoalkylated basic amino acid building blocks work described herein by the Torrey Pines Institute for Molecular Studies (TPIMS) start-up fund to P.C. We are especially thankful to Dr. Stanislaw F. Wnuk and Yong Liang from Florida International University for their assistance with NMR experiments. Also, we thank our colleague Dr. Mare Cudic for helpful comments and Ms. Karen Gottwald for editing the text.

Supplementary material

726_2012_1336_MOESM1_ESM.pdf (4.8 mb)
Supplementary material 1 (PDF 4941 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Jean-Philippe Pitteloud
    • 1
  • Nina Bionda
    • 1
    • 2
  • Predrag Cudic
    • 1
    Email author
  1. 1.Torrey Pines Institute for Molecular StudiesPort St. LucieUSA
  2. 2.Department of Chemistry and BiochemistryFlorida Atlantic UniversityBoca RatonUSA

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