Since the discovery of the antitumour properties of cisplatin (cis-Pt(Cl2(NH3)2) by Rosenberg, the square-planar platinum(II) and palladium(II) complexes have become of increasing importance in the design of new anticancer agents. The Pt(II) polyamine chelates in particular, have lately been the target of intense research due to the recognised enhancement of their cytotoxic effect in comparison to the currently used drugs. In fact, many of these second generation Pt(II) complexes were found to yield DNA adducts displaying long-distance intra- and interstrand cross-links, not available to the conventional mononuclear platinum compounds previously known. Moreover, the cytotoxic potency of these polyamine-bridged chelates showed to be strongly dependent on their structural characteristics and renders this series of compounds worth studying, their synthesis being carefully designed in order to test the effect of particular structural changes on their capacity as anticancer agents.
The presently proposed project aims at the study of new polynuclear Pd(II) complexes with biogenic polyamines (putrescine (H2N(CH2)4NH2), spermidine (H2N(CH2)3NH(CH2)4NH2) and spermine (H2N(CH2)3NH(CH2)4NH(CH2)3NH2)) – differing in the geometry and coordination type – in a twofold way: a) determination of their structural characteristics and reactivity involving important biological targets; b) study of their distribution within the cell, as a funtion of concentration and time of exposure to the drug.
The main methods used will be: vibrational spectroscopy, theoretical calculations, crystallography, electrochemical techniques and cytotoxic evaluation assays. The structural preferences of the complexes will be determined by crystallography and vibrational spectroscopy – FTIR, Raman and INS (inelastic neutron scattering) – coupled to quantum mechanical calculations. The electrochemical experiments will enable a better understanding of the in vivo behaviour of the compounds under study. The interaction of these new compounds with DNA – by conventional Raman and SERS experiments – will also be investigated, as well as their distribution and effect within the cell – through the observation of the living cells in the absence and presence of the complexes. Theoretical methods will also be used to predict structure and stabilities of Pd-DNA complexes. Their growth-inhibition and cytotoxic properties towards distinct human cancer cell lines will be simultaneously evaluated, and the mechanisms of action determined, the results thus obtained being compared with the homologous Pt(II) compounds and the chemotherapeutic agents in clinical use. The influence of factors like the nature of the metal (Pt/Pd), the size of the polyamine-bridge and the coordination type on the anticancer activity will be evaluated using the exploratory chemometric technique Two Level Factorial Design. The changes on calculated and experimental parameters as a function of the above factors will be analyzed using chemometric multivariate techniques. The structure-activity relationship will be created by different regression methods like Multiple Linear Regression (MLR), Principal Component Regression (PCR) and Partial Least Square (PLS).
The final goal of the present project is the development of new anticancer drugs, displaying a higher (and hopefully selective) cytotoxic activity and an optimised therapeutic efficacy, as well as the capacity of overcoming resistance to clinically used agents. This comes as a natural consequence of the on-going research work carried out by the elements of the team on the free polyamines and their Pt(II) chelates (POCTI/33199/QUI/00 and POCTI/QUI/47256/02).
State
Finished
Period
2009 to 2012
Funding
149.989,00 €
Project code
PTDC/QUI/66701/2006
Funding Entity
Portuguese Foundation for Science and Technology (FCT), Portugal
Members
Maria Paula Matos Marques Catarro (Principal Investigator)
Luís Alberto Esteves Batista de Carvalho
Ana Margarida Amado Roque Batista
Ana Lúcia Marques Batista de Carvalho
Publications