ISBN: 978-83-60043-10-3 - eurobic9

Eurobic9, 2-6 September, 2008, Wrocław, Poland
SL8. Peptide Hydroxamic Acids – Versatile Ligands for Metal Ions
P. Buglyó a , E. Farkas a , E. Csapó a , E.M. Nagy a , D. Sanna b and G. Pappalardo c
a
Department of Inorganic & Analytical Chemistry, University of Debrecen, H-4010 Debrecen, Hungary
b
Istituto C.N.R. di Chimica Biomolecolare, Sezione di Sassari, Trav. La Crucca 3 Reg. Baldinca, I-07040
Sassari, Italy
c
Istituto per lo Studio delle Sostanze Naturali di Interesse Alimentare e Chimico Farmaceutico, CNR, Catania,
Italy
e-mail: buglyo@delfin.unideb.hu
Peptide hydroxamic acids consist of a peptide chain and a hydroxamic (-CON(R)OH) function at the C terminus.
The most remarkable feature of these ligands obtained via hydroxyamidation of the corresponding oligopeptide
is the selective metal ion binding which is one important reason for their inhibitory effect on numerous
metalloproteinase enzymes. For design of effective enzyme inhibitors based on peptide hydroxamic acids the
knowledge of the most important factors determining the strength of interaction with metal ions is crucial. In
order to design effective inhibitors a systematic study has started in our laboratories with the synthesis of this
type of ligands and with the study of their metal ion binding capabilities.
Combining a peptide chain and a hydroxamic function there are numerouos coordination sites available for metal
binding in these ligands providing high selectivity for the metals.
Beside the hydroxamate, the terminal amino group, the amide
nitrogen of the peptide group(s) and the side chain donors present
in the molecule can also take part in the metal ion binding.
While primary hydroxamic acids (R3 = H) are capable to form
hydroximato type chelates with soft metal ions after
deprotonation and co-ordination of the hydroxamate NH, the
alkyl substituted secondary hydroxamic acids can only form
hydroxamato [O, O] type complexes. In order to obtain information about the role of the terminal amino group in
metal binding the corresponding non-protected and Z-protected ligand pairs were synthesized and studied.
Beside simple (AlaAla) dipeptide hydroxamic acids, the tripeptide analogues were also prepared and
investigated to explore the role of the peptide amide(s) of the molecule in the interaction with metal ions.
Since the imidazole moiety is one of the most important binding site in peptides it may significantly influence
the strength and selectivity of metal ion binding in peptide hydroxamates too. To explore this field new,
histidine-containing di- and tripeptide hydroxamates were synthesized and investigated.
In all cases pH-potentiometry was applied to determine the protonation constants of the ligands as well as the
stoichiometry and stability constants of the metal complexes formed in aqueous solution. In order to obtain
reliable information on the most probable solution structure of the associates in the metal ion containing systems
combined spectroscopic (NMR, EPR, UV-VIS, CD, ESI-MS) techniques were used.
The lecture will summarise the most important trends which were found in the interaction of these ligands with
biologically relevant (Fe(III), Cu(II), Ni(II), Zn(II), Al(III), Mo(VI)) metal ions.
Acknowledgement: This research was supported by the Hungarian Scientific Research Fund (OTKA T 046366,
T 049612).
References:
[1] P. Buglyó, E.M. Nagy, E. Farkas, I. Sóvágó, D. Sanna and G. Micera, Polyhedron, , 26, 1625, (2007).
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60
H 2N
R 1
O
H
N
R 2
O
N
R 3
OH
n n = 1, 2