Marta E. Alberto

The Second-Generation Anticancer Drug Nedaplatin: A Theoretical Investigation on the Hydrolysis Mechanism

The hydrolysis reaction processes of the second-generation platinum derivative Nedaplatin have been studied using density functional theory (DFT) combined with the conductor-like dielectric continuum model (CPCM) approach, in order to obtain detailed data on its mechanism of action. The first and the second hydrolysis of Nedaplatin, corresponding to the ring opening followed by the loss of the ligand, respectively, have been explored in neutral and acid conditions. The influence of an extra water molecule which could assist the degradation processes has also been considered including in our models an explicit water molecule other than the reactive one. The computed potential energy surfaces show that the rate limiting step in neutral conditions is the first hydrolysis process and, consequently, the double hydrated complex is suggested to be the species reacting with the DNA purine bases, while in acid conditions the trend is different, with the second hydrolysis process being the rate limiting step. The results obtained in this work allow us to make a comparison with the trends previously found for the other platinum anticancer drugs currently used in the medical protocols.

Neutral and Acidic Hydrolysis Reactions of the Third Generation Anticancer Drug Oxaliplatin

The hydrolysis of oxaliplatin, a third generation anticancer drug, is expected to play an important role in the activation of this compound before it reaches DNA. The first and second hydrolysis corresponding to the addition of the first water molecule concomitant with the ring-opening, followed by addition of a second water and loss of the monodentate oxalato ligand, respectively, were studied combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The reaction was studied in neutral and acidic conditions, and all stationary points have been identified. The computed potential energy surfaces show that, for the neutral hydrolysis, the ring-opening reaction is the rate-limiting process, with an activation barrier of about 28 kcal/mol. For the acid degradation in water, according to experimental data, the reaction is expected to proceed in a faster biphasic process, and the rate-limiting process is the ligand detachment that occurs with a barriers of about 22 kcal/mol. According to the calculated results, we expect that the reaction is favored in acidic conditions and that the monoaquated complex should be the species reacting with DNA.

Which One among the Pt-Containing Anticancer Drugs More Easily Forms Monoadducts with G and A DNA Bases? A Comparative Study among Oxaliplatin, Nedaplatin, and Carboplatin

The platination processes of DNA bases with second- and third-generation Pt(II) anticancer drugs have been investigated using density functional theory (DFT) combined with the conductor-like dielectric continuum model (CPCM) approach, in order to describe their binding mechanisms and to obtain detailed data on the reaction energy profiles. Although there is no doubt that a Pt-N7 bond forms during initial attack, the energetic profiles for the formation of the monofunctional adducts are not known. Herein, a direct comparison between the rate of formation of the monofunctional adducts of the second- and third-generation anticancer drugs with guanine (G) and adenine (A) DNA bases has been made in order to spotlight possible common or different behavior. The guanine as target for platination process is confirmed to be preferred over adenine for all the investigated compounds and for both the hydrolyzed forms considered in our investigation. The preference for G purine base is dominated by electronic factors and promoted by a more favorable hydrogen-bonds pattern, confirming the important role played by H-bonds in determining both structural and kinetic control on the purine platination process.

Theoretical Determination of Electronic Spectra and Intersystem Spin-Orbit Coupling: The Case of Isoindole-BODIPY Dyes.

Density functional theory and its time-dependent extension (DFT, TDDFT) has been herein employed to elucidate the structural and electronic properties for a series of isoindole-boron dipyrromethene (isoindole-BODIPY) derivatives. The role played by both the nature and the positions of the substituents on intersystem spin-crossing has been investigated computing the spin-orbit matrix elements between singlet and triplet excited state wave functions weighted by the TDDFT transition coefficients. Their potential therapeutic use as photosensitizers in photodynamic therapy (PDT) is proposed on the basis of their strong absorbance in the red part of the visible spectrum, vertical triplet energies resulting higher than 0.98 eV, and the spin-orbit matrix elements that result to be comparable with different drugs already used in PDT.

The catalytic mechanism of protein phosphatase 5 established by DFT calculations.

In order to elucidate the catalytic mechanism of the Mn-Mn containing serine/threonine protein phosphatase 5 (PP5), we present a density functional theory study with a cluster model approach. According to our results, the reaction occurs through an in-line concerted transition state with an energy of 15.8 kcal mol(-1) , and no intermediates are formed. The important role played by His304 and Asp274 as stabilizers of the leaving group has been shown, whereas the role played by the metal ions seems to be mostly electrostatic. The indispensable requirement of having a neutral active center has been demonstrated by testing different protonation states of the cluster model. We have shown also the importance of describing properly the electronic configuration of the Mn-Mn binuclear centers.

Atomistic details of the Catalytic Mechanism of Fe(III)-Zn(II) Purple Acid Phosphatase.

In the present work, we performed a theoretical investigation of the reaction mechanism of the Fe(III)-Zn(II) purple acid phosphatase from red kidney beans (rkbPAP), using the hybrid density functional theory and employing different exchange-correlation potentials. Characterization of the transition states and intermediates involved and the potential energy profiles for the reaction in different environments (gas phase, protein environment, and water) are reported. Our results show that the Fe(III)-Zn(II)PAP catalyzes the hydrolysis of methylphosphate via direct attack by a bridging metals-coordinated hydroxide leading to the cleavage of the ester bond. From our study emerges that the rate-limiting step of the reaction is the nucleophilic attack followed by the less energetically demanding release of the leaving group. Furthermore, we provide insights into some important points of contention concerning the precatalytic complex and the substrate coordination mode into the active site prior to hydrolysis. In particular: (i) Two models of enzyme-substrate with different orientations of the substrate into the active site were tested to evaluate the possible roles played by the conserved histidine residues (His 202 and His 296); (ii) Different protonation states of the substrate were taken into account in order to reproduce different pH values and to verify its influence on the catalytic efficiency and on the substrate binding mode; (iii) The metals role in each step of the catalytic mechanism was elucidated. We were also able to ascertain that the activation of the leaving group by the protonated His 296 is decisive to reach an optimal catalytic efficiency, while the bond scission without activation requires higher energy to occur.

Photophysical origin of the reduced photodynamic therapy activity of temocene compared to Foscan®: insights from theory

In order to explain the reduced photodynamic (PDT) activity of a recently proposed m-tetra (hydroxyphenyl) porphycene derivative (temocene or THPPo) in terms of singlet oxygen quantum yields compared to porphyrin analogue Foscan (m-THPC), a time dependent DFT investigation has been carried out. Computed electronic transitions, singlet-triplet energy gaps and spin-orbit coupling matrix elements (SOCME) can be related to the reduced PDT activity.

Electronic spectra and intersystem spin-orbit coupling in 1,2- and 1,3-squaraines

The main photophysical properties of a series of recently synthetized 1,2‐ and 1,3‐squaraines, including absorption electronic spectra, singlet‐triplet energy gaps, and spin‐orbit matrix elements, have been investigated by means of density functional theory (DFT) and time‐dependent DFT approaches. A benchmark of three exchange‐correlation functionals has been performed in six different solvent environments. The investigated 1,2 squaraines have been found to possess two excited triplet states (T1 and T2) that lie below the energy of the excited singlet one (S1). The radiationless intersystem spin crossing efficiency is thus enhanced in both the studied systems and both the transitions could contribute to the excited singlet oxygen production. Moreover, they have a singlet‐triplet energy gap higher than that required to generate the cytotoxic singlet oxygen species. According to our data, these compounds could be used in photodynamic therapy applications that do not require high tissue penetration.

Can human prolidase enzyme use different metals for full catalytic activity

The catalytic hydrolysis of the Gly-Pro substrate by the bimetallic prolidase active site model cluster has been investigated at the DF/B3LYP level of theory, in order to provide fundamental insights into the still poorly understood mechanism of prolidase catalysis. To date, the majority of prolidases exhibits metal-dependent activity, requiring two divalent cations such as Zn(2+), Mn(2+), or Co(2+) for maximal activity. In addition, it has been shown recently that two different metal ions in the active site of human prolidase (Zn and Mn) can coexist, with the protein remaining partially active. With the purpose of identifying which is the most efficient dimetallic center for the prolidase catalyzed reaction, Zn(II), Co(II), and Mn(II) have been examined as potential catalytic metals for this enzyme. Furthermore, to better elucidate the exact roles played by the metals occupying the site 1 and site 2 positions, the hetero-bimetallic active site having Zn and Mn cations has been also investigated, considering the two derivatives Mn1-Zn2 and Zn1-Mn2. The rate-determining step of the hydrolysis reaction is always found to be the nucleophilic addition of the hydroxide ion on the carbonyl carbon of the scissile peptide bond, followed by the less energetically demanding proline-peptide C-N bond scission. The analysis of the involved energy barriers does not indicate clearly a preference for a particular metal by the prolidase enzyme. Instead, we may point out a slightly better behavior of the cobalt-containing cluster as far as both tetrahedral formation and its decomposition are concerned, due to a greater degree of ligands-to-metals charge transfer. The mixed Mn-Zn hetero-dimetallic clusters appear to be also able to perform the hydrolysis of the Pro-Gly substrate, with a slight preference for the Mn1-Zn2 configuration.

The Degradation Pathways in Chloride Medium of the Third Generation Anticancer Drug Oxaliplatin

We have investigated the degradation reactions, in chloride medium, of the third generation drug oxaliplatin using density functional theory. Our calculations confirm that this drug should be administered in chloride free solutions, and we have ascertained the main biodegradation products upon chloride binding, which are essential to establish the active compounds reacting with DNA. In addition, detailed knowledge of these platinum complexes is fundamental for correct elimination procedures in wastewater treatments.