Luís A. E. Batista de Carvalho

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.

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).

Decavanadate, decaniobate, tungstate and molybdate interactions with sarcoplasmic reticulum Ca2+-ATPase : quercetin prevents cysteine oxidation by vanadate but does not reverse ATPase inhibition

Recently we demonstrated that the decavanadate (V(10)) ion is a stronger Ca(2+)-ATPase inhibitor than other oxometalates, such as the isoelectronic and isostructural decaniobate ion, and the tungstate and molybdate monomer ions, and that it binds to this protein with a 1 : 1 stoichiometry. The V(10) interaction is not affected by any of the protein conformations that occur during the process of calcium translocation (i.e. E1, E1P, E2 and E2P) (Fraqueza et al., J. Inorg. Biochem., 2012). In the present study, we further explore this subject, and we can now show that the decaniobate ion, [Nb(10) = Nb(10)O(28)](6-), is a useful tool in deducing the interaction and the non-competitive Ca(2+)-ATPase inhibition by the decavanadate ion [V(10) = V(10)O(28)](6-). Moreover, decavanadate and vanadate induce protein cysteine oxidation whereas no effects were detected for the decaniobate, tungstate or molybdate ions. The presence of the antioxidant quercetin prevents cysteine oxidation, but not ATPase inhibition, by vanadate or decavanadate. Definitive V(IV) EPR spectra were observed for decavanadate in the presence of sarcoplasmic reticulum Ca(2+)-ATPase, indicating a vanadate reduction at some stage of the protein interaction. Raman spectroscopy clearly shows that the protein conformation changes that are induced by V(10), Nb(10) and vanadate are different from the ones induced by molybdate and tungstate monomer ions. Here, Mo and W cause changes similar to those by phosphate, yielding changes similar to the E1P protein conformation. The putative reduction of vanadium(V) to vanadium(IV) and the non-competitive binding of the V(10) and Nb(10) decametalates may explain the differences in the Raman spectra compared to those seen in the presence of molybdate or tungstate. Putting it all together, we suggest that the ability of V(10) to inhibit the Ca(2+)-ATPase may be at least in part due to the process of vanadate reduction and associated protein cysteine oxidation. These results contribute to the understanding and application of these families of mono- and polyoxometalates as effective modulators of many biological processes, particularly those associated with calcium homeostasis.

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.

Guanine: A Combined Study Using Vibrational Spectroscopy and Theoretical Methods

The present paper reports a conformational study of solid-state anhydrous guanine, using vibrational spectroscopy techniques—infrared, Raman, and inelastic neutron scattering—coupled to quantum mechanical methods at the DFT level, both for the isolated molecule and the condensed state. In both cases, the 7H-keto-amino tautomer was found to be the prevalent form, contrary to aqueous solutions and hydrated polycrystalline guanine, where the 9H-keto-amino tautomer is the most favoured species. This paper is a significant contribution for the existing spectroscopic characterization of this purine base, by unambiguously assigning its vibrational spectra.

Polymorphism in Cisplatin Anticancer Drug

This study reports a combined experimental and theoretical study of the solid-state polymorphism of the anticancer agent cisplatin. A complete assignment was performed for the inelastic neutron scattering (INS) and Raman spectra collected simultaneously for cisplatin, at different temperatures, with a view to obtain reliable and definitive evidence of the relative thermal stability of its α and β polymorphic species. A marked temperature-dependent hysteresis was observed, as previously reported in the literature. Theoretical calculations were carried out at the density functional theory level, using a plane-wave basis set approach and pseudopotentials. A detailed comparison with the experimental Raman and INS data showed that the α polymorph is present at the lowest temperatures, whereas the β form occurs near room temperature. Furthermore, regions of coexistence of both forms are identified, which depend on the working mode (heating or cooling). These findings imply that Raman spectroscopy allows clear identification of the α and β polymorphs at a given temperature and can unambiguously discriminate between them. Elucidation of the polymorphic equilibrium of this widely used anticancer drug is paramount for its pharmaceutical preparation and storage conditions.

Inelastic Neutron Scattering Study of PtII Complexes Displaying Anticancer Properties

The well-known platinum(II) chemotherapeutic drugs cisplatin [cis-(NH(3))(2)PtCl(2)] and carboplatin [Pt(NH(3))(2)C(6)O(4)H(6)], as well as the analogous transplatin [trans-(NH(3))(2)PtCl(2)], were studied by inelastic neutron scattering (INS) spectroscopy, coupled to quantum mechanical methods, and some ancillary work with X-ray diffraction on powders. An assignment of the experimental spectra was carried out based on the calculated INS transition frequencies and intensities (at the DFT level), thereby achieving a good correspondence between the calculated and observed data. Unusually good-quality INS spectra were obtained from about 250 mg, which is the smallest sample of a hydrogenous compound for which a successful INS interpretation has been reported. The knowledge of the local configuration of this kind of complexes is essential for an accurate understanding of their activity, which will pave the way for the rational design of novel third-generation drugs comprising cisplatin- and carboplatin-like moieties.

Characterization of decavanadate and decaniobate solutions by Raman spectroscopy

The decaniobate ion, (Nb10 = [Nb10O28](6-)) being isoelectronic and isostructural with the decavanadate ion (V10 = [V10O28](6-)), but chemically and electrochemically more inert, has been useful in advancing the understanding of V10 toxicology and pharmacological activities. In the present study, the solution chemistry of Nb10 and V10 between pH 4 and 12 is studied by Raman spectroscopy. The Raman spectra of V10 show that this vanadate species dominates up to pH 6.45 whereas it remains detectable until pH 8.59, which is an important range for biochemistry. Similarly, Nb10 is present between pH 5.49 and 9.90 and this species remains detectable in solution up to pH 10.80. V10 dissociates at most pH values into smaller tetrahedral vanadate oligomers such as V1 and V2, whereas Nb10 dissociates into Nb6 under mildly (10 > pH > 7.6) or highly alkaline conditions. Solutions of V10 and Nb10 are both kinetically stable under basic pH conditions for at least two weeks and at moderate temperature. The Raman method provides a means of establishing speciation in the difficult niobate system and these findings have important consequences for toxicology activities and pharmacological applications of vanadate and niobate polyoxometalates.

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.