Sónia M. Fiuza

Conformational and vibrational study of platinum(II) anticancer drugs : cis-diamminedichloroplatinum (II) as a case study

A conformational and vibrational analysis of cisplatin [cis-diamminedichloro-platinum(II)] (cDDP) is reported. Several theory methods (from Hartree-Fock to Moller-Plesset and density functional theory) combined with different all-electron basis sets are evaluated, in view of determining the best suited strategy for accurately representing this molecule. This choice is based on the best compromise between accuracy and computational requirements. Different scaling models of the cDDP vibrational modes were tested for obtaining the best scaling factors to be used in this type of inorganic systems. The structural parameters and vibrational results predicted by the calculations are compared with the corresponding experimental data, namely, x-ray structure, and Raman and inelastic neutron scattering spectra. Finally, a complete assignment of the cDDP vibrational spectra is presented.

DNA interaction with palladium chelates of biogenic polyamines using atomic force microscopy and voltammetric characterization.

The interaction of double-stranded DNA with two polynuclear Pd(II) chelates with the biogenic polyamines spermidine (Spd) and spermine (Spm), Pd(II)-Spd and Pd(II)-Spm, as well as with the free ligands Spd and Spm, was studied using atomic force microscopy (AFM) at a highly oriented pyrolytic graphite (HOPG) surface, voltammetry at a glassy carbon (GC) electrode, and gel electrophoresis. The AFM and voltammetric results showed that the interaction of Spd and Spm with DNA occurred even for a low concentration of polyamines and caused no oxidative damage to DNA. The Pd(II)-Spd and Pd(II)-Spm complexes were found to induce greater morphological changes in the dsDNA conformation, when compared with their ligands. The interaction was specific, inducing distortion and local denaturation of the B-DNA structure with release of some guanine bases. The DNA strands partially opened give rise to palladium intra- and interstrand cross-links, leading to the formation of DNA adducts and aggregates, particularly in the case of the Pd(II)-Spd complex.

Pt(II) vs Pd(II) Polyamine Complexes as New Anticancer Drugs: A Structure- Activity Study

Two homologous trinuclear polyamine chelates with either Pt(II) (Ia) or Pd(II) (Ib) were screened for their anticancer properties. Their growth-inhibition activity towards a human tongue epithelioma (HSC-3) was assessed in vitro, and the effect of the cation alteration was determined (IC50=32 μM for Ib vs 66 μM for Ia).

Biologic activity of a dinuclear Pd(II)-spermine complex toward human breast cancer

A dinuclear palladium‐based complex (Pd2‐Spm) was synthesized and compared with cisplatin (cDDP) on two different human breast cancer cell lines (MCF‐7 and MDA‐MB‐231) as well as toward an untransformed cell line (BJ fibroblasts). The results obtained show that Pd2‐Spm is more effective against the estrogen receptors [ER(−)] cell line MDA‐MB‐231, while cDDP displayed better results for the ER(+) MCF‐7 cell line. It was shown that, like cDDP, Pd2‐Spm triggers phosphorylation of H2AX, indicating that this compound damages DNA. Apart from DNA, Pd2‐Spm also targets the cytoskeleton having a greater impact on cell morphology than cDDP. Pd2‐Spm and cDDP have opposite antiproliferative activities in the presence of the PI3K inhibitor wortmannin. Furthermore, Pd2‐Spm at an optimized concentration displays a rapid antiproliferative effect as opposed to cDDP, which seems to have a slower kinetics. The results point to a distinct mechanism of action for each of these complexes, which may explain their synergistic action when coadministrated.

Use of Effective Core Potential Calculations for the Conformational and Vibrational Study of Platinum(II) Anticancer Drugs. cis-Diamminedichloroplatinum(II) as a Case Study

In the light of the recognized anticancer properties of cisplatin-type inorganic systems, the exact knowledge of their conformational preferences is of the utmost importance for understanding their biological activity. The present study reports the use of theoretical (quantum mechanical) calculations for achieving this goal. An alternative calculation method to the use of the AE basis sets, both accurate and computationally feasible, was presently tested for the conformational and vibrational study of cis-diamminedichloroplatinum(II). Effective core potentials (ECPs) were used, within the HF methodology and, within the B3LYP and mPW1PW DFT protocols. The DFT methods (particularly mPW1PW) were found to be the best choice for describing cDDP (as compared to the HF methodology).

Effect of the Metal Center on the Antitumor Activity of the Analogous Dinuclear Spermine Chelates (PdCl2)2(Spermine) and (PtCl2)2(Spermine)

The cytotoxic activity of (PdCl2)2(spermine) against a human cancer cell line (HSC-3) was evaluated. The re- sults show an activity higher than that of the analogous Pt(II) chelate and, for 24 h incubations, identical to that of cis- platin. They also suggest a faster intracellular uptake and DNA binding relative to cisplatin.

Helianthus tuberosus and polyamine research: Past and recent applications of a classical growth model

The earliest studies concerning polyamines (PAs) in plants were performed by using in vitro cultured explants of Helianthus tuberosus dormant tuber. This parenchyma tissue was particularly useful due to its susceptibility to several growth substances, including PAs. During tuber dormancy, PA levels are too low to sustain cell division; thus Helianthus represents a natural PA-deficient model. When cultivated in vitro in the presence of auxins, Helianthus tuber dormant parenchyma cells at the G(0) stage start to divide synchronously acquiring meristematic characteristics. The requirement for auxins to induce cell division can be substituted by aliphatic PAs such as putrescine, spermidine or spermine. Cylinders or slices of explanted homogeneous tuber parenchyma were cultured in liquid medium for short-term studies on the cell cycle, or on solid agar medium for long-term experiments. Morphological and physiological modifications of synchronously dividing cells were studied during the different phases of the cell cycle in relation to PAs biosynthesis and oxidation. Long-term experiments led to the identification of the PAs as plant growth regulators, as the sole nitrogen source, as tuber storage substances and as essential factors for morphogenetic processes and cell homeostasis. More recently this system was used to study the effects on plant cell proliferation of platinum- or palladium-derived drugs (cisplatin and platinum or palladium bi-substituted spermine) that are used in human cancer cell lines as antiproliferative and cytotoxic agents. Cisplatin was the most active both in cell proliferation inhibition and on PA metabolism. Similar experiments were performed using three agmatine analogous. Different effects of these compounds were observed on cell proliferation, free PA levels and enzyme activities, leading to a hypothesis of a correlation between their chemical structure and the agmatine metabolism in plants.

Increased breast cancer cell toxicity by palladination of the polyamine analogue N-1,N-11-bis(ethyl)norspermine

Breast cancer is one of the most common malignant tumor forms among women and many women succumb to their disease. Thus, new anticancer agents that can efficiently improve patient survival are of the utmost importance. In this study, the effects of the polyamine analogues N1,N11-bis(ethyl)norspermine (BENSpm) and N1-cyclo-propylmethyl-N11-ethylnorspermine (CPENSpm) and the synthesized dinuclear complexes Pd2BENSpm (Pd-BENSpm), Pt2CPENSpm (Pt-CPENSpm) and Pd2Spm (Pd-Spm) were investigated in normal-like breast epithelial MCF-10A cells and the breast cancer cell lines JIMT-1 and L56BR-C1. The overall data show that palladination of BENSpm resulted in enhanced cytotoxicity, in contrast to platination of CPENSpm that reduced cytotoxicity, which might be explained by differences in the cellular uptake of Pd-BENSpm and Pt-CPENSpm. BENSpm and Pd-BENSpm treatment reduced the CD44+CD24− putative cancer stem cell population, evaluated by flow cytometry. Furthermore, Pd-BENSpm was the most efficient compound regarding induction of DNA damage and decrease in colony formation in soft agar. Pt-CPENSpm and Pd-Spm, on the other hand, were shown to be the least toxic compounds of all tested. Pd-Spm efficiently reduced the cellular glutathione levels, which probably was a consequence of its metabolic inactivation by conjugation to this endogenous thiol. The normal-like cells were found to be less sensitive to the agents than the breast cancer cells. Our findings show that Pd-BENSpm exhibits promising anticancer effects which render it suitable for further optimization to develop a new metal-based chemotherapeutic drug for breast cancer treatment.

Conformational and vibrational study of cis-diamminedichloropalladium(II).

A conformational and vibrational analysis of cis-diamminedichloropalladium(ii) (cDDPd) is reported. Several theoretical methods (from Hartree-Fock to Møller-Plesset and Density Functional Theory) combined with different all-electron basis-sets are evaluated, in view of determining the best suited strategy for accurately representing this molecule. This choice is based on the best compromise between accuracy and computational requirements. Different scaling models were tested for obtaining the best scaling schemes of the vibrational modes to be used in this type of inorganic systems. The structural parameters and vibrational results predicted by the calculations are compared with the corresponding experimental data, namely X-ray structure and vibrational spectra. Finally, a complete assignment of the cDDPd vibrational spectra is presented.

Pt(II) Complexes with Linear Diamines—Part I: Vibrational Study of Pt-Diaminopropane

A conformational analysis of the Pt(dap)Cl2 complex (dap=1,3-diaminopropane) was performed by vibrational spectroscopy (FTIR, Raman, and INS), coupled to quantum mechanical methods within the density functional theory (DFT) and effective core potential (ECP) approaches. A complete spectral assignment of the system was achieved, due to the combined use of all available vibrational spectroscopic techniques. A good agreement was found between experimental and theoretical results, as well as with reported data for analogous complexes (e.g., cisplatin).