4th EucheMs chemistry congress

wednesday, 29-Aug 2012
s715
chem. Listy 106, s587–s1425 (2012)
life sciences
Medicinal Chemistry session – i
o - 3 2 3
PoLyoxoMetALAteS AS verSAtiLe enzyMe
inhiBitorS
h. StePhAn 1 , C. e. MüLLer 2
1 Helmholtz-Zentrum Dresden-Rossendorf,
Institute of Radiopharmacy, Dresden, Germany
2 Universität Bonn, Pharmaceutical Institute, Dresden, Germany
Polynuclear metal compounds may have considerable
potential as metallic drugs. The most prominent representatives
are polyoxometalates (POMs) which have been investigated since
the last third of the 19th century. In addition to applications in
catalysis, separation, analysis, and as electron-dense imaging
agents, some of these substances have been shown to exhibit
biological activity in vitro as well as in vivo ranging from anticancer,
antibiotic, and antiviral to anti-diabetic effects.
Polyoxometalates represent a diverse ensemble of
nanostructures with an almost infinite variability of chemical,
physical and biological properties. The size of typical covalent
bridged cluster compounds is in the range from 1 to 3 nm. The
attachment of special surface groups on the periphery of cluster
compounds may result in self-assembled non-covalent organized
structures larger than 5 nm which are characteristic for biomolecules,
such as enzymes. Cells of mammalian organisms are
typically 10 to 30 µm. However, sub-cellular organelle
dimensions are smaller and range in sub-µm sizes. This
comparison of size dimension illustrates that polymetalates are
small enough to allow the cell membrane to be penetrated without
too much interference. Evidently, some types of polyoxometalates
are able to be transported into cells, particularly into mitochondria.
However, many of such polyanions are only slightly taken up by
cells, obviously caused by negatively charged membranes.
On the way to explore the biological activity of polynuclear
cluster compounds, we recently recognised POMs as a new class
of potent enzyme inhibitors. Certain polyanionic complexes are
able to inhibit extracellular E-NTPDases (ecto-nucleoside
triphosphate diphosphohydrolases) that are surface-located
nucleotide-hydrolyzing enzymes involved in the regulation of
signaling cascades by activating P2 (nucleotide) receptors.
We want to present a brief overview about the potential of
POMs as E-NTPDase inhibitors and P2 receptor antagonists.
Keywords: Enzyme; Inhibitors; Polyoxometalates;
Medicinal Chemistry session – i
4 th EucheMs chemistry congress
o - 3 2 4
CyCLAMMonoProPioniC ACid- A ProMiSinG
CheLAtinG SySteM for rAdioCoPPer iSotoPeS
M. KuBeiL 1 , L. PeSCheL 1 , h. StePhAn 1 ,
J. SteinBACh 1
1 Helmholtz-Zentrum Dresden-Rossendorf,
Institute of Radiopharmacy, Dresden, Germany
A wide variety of radiometal-chelating bioconjugates have
been studied intensively to design effective radiopharmaceuticals
for diagnostic and therapeutic purposes. Azamacrocycles offer an
enormous potential to achieve highly stable radiometal complexes
and allow the covalent attachment of targeting and/or fluorescence
units at the ligand skeleton. In this context, 1,4,8,11-
-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) is
quite often used for the development of copper-based
target-specific radiopharmaceuticals, although demetallation and
transchelation occur in biological systems. In contrast,
radiolabeling of propionic acid analogues has not been reported
so far.
An appropriate building block to form very stable
complexes with copper(II) is N-mono-(2-(carboxy)ethyl)-
-1,4,8,11-tetraazacyclotetradecane (Cyclammonopropionic acid,
CMPA) which permits the formation of stable radiocopper
complexes as well as a facile approach to obtain peptide
multimers. An improved pharmaceutical targeting might be
utilized due to the multimeric peptide functionalization of the
chelating agent. The Epidermal-Growth-Factor-Receptor (EGFR),
which is overexpressed on a multitude of tumors, has been chosen
as target system to be studied.
Herein, we want to report about coupling reactions of the
model dipeptide H-(L)-Leu-(L)-Ala-OH, which is a part of an
EGFR-specific peptide, with the cyclammonopropionic acid
skeleton. Radiolabeling of CMPA-peptide conjugates with
copper-64 indicate high in vitro stability of the complexes formed.
So far, this promising behavior may pave the way to develop
attractive candidates for radiopharmaceutical applications.
Keywords: chelates; copper; peptide; radiopharmaceutical;
AUGUst 26–30, 2012, PrAGUE, cZEcH rEPUbLIc