Book of Abstracts - Ruhr-Universität Bochum

P-05
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Solid-State Synthesis of Peptide-Tethered Pt(IV) Complexes
and Their Cytotoxic Properties
Sergey Abramkin, a Markus Galanski, a and Bernhard Keppler *a
a University of Vienna, Faculty of Chemistry, Department of Inorganic Chemistry, Währingerstrase
42, 1090, Vienna, Austria. E-mail: sergey.abramkin@univie.ac.at
Platinum-based drugs play an essential role in cancer treatment since the discovery of the anticancer
drug cisplatin. Subsequent development of complexes resulted in three generations of drugs, the last
one to be approved by the FDA was oxaliplatin. Side effects remain one of the main shortcomings of
chemotherapy, arising from lack of specificity and inefficient cell entry.
Short peptides can be used for targeting and transportation of drug molecules. They can change not
only the basic parameters like lipophilicity or water solubility, but even more complex interactions of
drugs with the microenvironment can be influenced. The axial ligands of Pt (IV) are the optimal site
for derivatization: upon reduction they are cleaved from the prodrug, and the Pt(II) complex is
released.
Inefficient cell entry is the reason for higher dosage of drugs, however stimulated uptake will increase
the amount of the drug, reaching the intracellular target. Cell-penetrating peptides can be used for
intracellular delivery of Pt complexes; the TAT peptide is the best studied example of this group.
Selectivity can be achieved using the peptides as delivery vectors. High expression of the GRP
receptor in many tumors (prostate, lung, breast) makes it an interesting target for platinum conjugates.
The short peptide bombesin was chosen for conjugation to Pt to investigate its influence on cytotoxic
properties.
H 2
N
N
H 2
O
Pt
O
O
O
O
O
O
O
O
O
OH
OH
R
R = TAT47-57(YGRKKRRQRRR) or Bombesin(QWAVGHLM)
Solid-phase synthesis is a commonly used method for the preparation of peptides and their conjugates.
Oxaliplatin was oxidized and two uncoordinated carboxyl groups were introduced, thereafter the
complex was reacted with polymer-bound TAT and bombesin. Cleavage with TFA and purification
afforded mono- and bisconjugates, characterized with ESI-MS, NMR and analytical HPLC. Synthesis
and cytotoxic properties will be presented.
The support of COST, the FWF, the FFG and the Austrian Council for Research and Technology
Development is gratefully acknowledged.
63
H 2
N
N
H 2
O
Pt
O
O
O
O
O
O
O
O
O
OH
+
R
H 2
N
N
H 2
O
Pt
O
O
O
O
O
O
O
O
O
R
R