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

Eurobic9, 2-6 September, 2008, Wrocław, Poland
SL14. New Pt(II) and Pt(IV) Complexes with Purine Ligands
as Precursors for Anticancer Drugs
I. Łakomska, E. Szłyk
Faculty of Chemistry, Nicolaus Copernicus University, ul. Gagarina 7, 87 100 Toruń, Poland,
e-mail: eszlyk@chem.uni.torun.pl
Presently used antitumor drugs, based on cisplatin mechanism, still need improvement due to the known side
effects. Hence the synthesis and structural characterization of platinum(II) complexes with new ligands along
with tests for antitumor activity is the purpose of our research. In our studies we have focused on 1,2,4triazolo[1,5-a]pyrimidine
derivatives, which have the structure similar to purine. Their fused ring system differs
in having the pyrimidine nitrogen atom in a bridgehead position with disappearance of the acidic H-proton of the
five-membered ring. Triazolopyrimidine derivatives ligands display versatility in their interaction with metal
ion, because they can bind the metal ion via different hetrocyclic nitrogen atoms and due to the impact on the
other ligands, either by electronic or steric factors. Pt(II) compounds, including cisplatin, are not orally active
and often lose their effectiveness in prolonged administration. Therefore a six-coordinate octahedral
platinum(IV) complexes, which reveal better solubility could be one of the possible ways to solve the problem.
The six-coordinated Pt(IV) predisposes towards ligands substitution by a dissociative mechanism versus the
associative mechanism for Pt(II). Moreover Pt(IV) compounds are more substitutionally inert, hence this is
desirable for oral bioavailability and reduction of toxicity, but is unfavorable for DNA intercalation.
Nonetheless, several platinum(IV) complexes show considerable activity in initial trials. Their functionality
depend on the in vivo reduction of Pt(IV) to Pt(II), producing reactive intermediates, that can interact with DNA.
Examination of the structure-activity relationship (SAR) indicates that biological activity of platinum(II) series
depended on the coordinated ligand. Studied complexes were structurally characterized by: 1 H, 13 C, 15 N, 195 Pt
NMR, IR, MS spectra and X-ray crystal structure analysis. One can suggests, that complexes with two
heterocycles in cis position are more active, than their cisplatin analogues. Examination of SAR, suggests, that
antitumor activity of platinum(IV) compounds containing 1,2,4-triazolo[1,5-a]pyrimidines correlates directly
with the size of the alkyl groups substituted on the heterocyclic ligands. The highest activity was observed for
complexes with tertbutyl group in 5,7 positions, in the pyrimidine ring. In the triazolopyrimidine family of
platinum(II) complexes the best activity against tumors cell lines has been detected for complexes with steric
hindrances in the triazolopyrimidine ring. In this case environment around platinum(II) ion influence the
antitumor activity The discussion of the structural parameters of Pt(II) and Pt(IV) complexes in function of their
antiproliferative activity in vitro against the cells of human cancer cell lines: T47D (breast cancer), A549 (nonsmall
cell lung carcinoma), HCV29T (bladder cancer) and SW707 (rectal adenocarcinoma) and MCF7, EVSa-
T, WIDR, IGROV, M19MEL, A498, H226 will be presented. It has been noted, that ID50 values for some of
the complexes are in range of the international activity criterion for synthetic agents (4 µg/ml), hence these
compounds may be considered as the agents for potential antitumor application.
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