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A new non-natural arginine-like amino acid derivative with a sulfamoyl group in the side-chain

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Abstract

Sulfamoylation of the l-ornithine methyl ester side-chain generates a non-natural arginine isostere which can be coupled with N-Fmoc-l-proline to synthesize analogues which maintain the structural characteristics of the biologically important Pro-Arg dipeptide sequence. As a probe of its biological importance, the sulfamoylated amino acid derivative was also incorporated as P1 residue in tripeptide structures matching the C-terminal subsequence of fibrinogen. The reported results demonstrate that the functionalization of l-ornithine side-chain with a neutral sulfamoyl group can generate an arginine bioisostere which can be used for the synthesis of prototypes of a new class of human thrombin inhibitors.

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Abbreviations

DMF:

N,N-Dimethylformamide

MTBE:

Methyl-tert-butyl-ether

DMAP:

4-(N,N-Dimethylamino)pyridine

DIEA:

N,N-Diisopropylethylamine

HOBt:

1-Hydroxybenzotriazole

EDCI:

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

TFA:

Trifluoroacetic acid

α-CHCA:

α-Cyano-4-hydroxy-trans-cynnamic acid

DEPT:

Distorsionless enhancement by polarization transfer

TOCSY:

Total correlation spectroscopy

DQF-COSY:

Double quantum filtered correlation spectroscopy

TLC:

Thin layer chromatography

FCC:

Flash column chromatography

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Acknowledgment

The presented work was financially supported by grants of the Ministero dell’Università e della Ricerca (MIUR, Italy). Authors gratefully acknowledge Dr. Soluzzo Cavalcanti for all suggestions and precious discussion about the anticoagulant activities.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Università della Calabria, Via P. Bucci, Cubo 15/C, 87036, Arcavacata di Rende (CS), Italy

    Rosaria De Marco, Maria L. Di Gioia, Antonella Leggio, Angelo Liguori, Francesca Perri, Carlo Siciliano & Maria C. Viscomi

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  1. Rosaria De Marco
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  2. Maria L. Di Gioia
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  3. Antonella Leggio
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  4. Angelo Liguori
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  5. Francesca Perri
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  6. Carlo Siciliano
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  7. Maria C. Viscomi
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Corresponding author

Correspondence to Angelo Liguori.

Electronic supplementary material

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726_2009_267_MOESM1_ESM.pdf

Supporting Information Available. Copy of 1H and 13C NMR spectra for compounds 2, 6, 8, 10, 12. Copy of 1H spectra for compounds 13 and 14. Copy of the 13C DEPT analysis and contour plots of the COSY and TOCSY spectra for compound 6. Copy of the contour plot of the TOCSY spectrum for dipeptide 12 (PDF 570 kb)

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De Marco, R., Di Gioia, M.L., Leggio, A. et al. A new non-natural arginine-like amino acid derivative with a sulfamoyl group in the side-chain. Amino Acids 38, 691–700 (2010). https://doi.org/10.1007/s00726-009-0267-2

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