Computational Study of Compounds with Biological Activity and their Interaction with Nano-Materials

In the last few decades, computer simulation became a potent tool to study experimental systems such as chemical reactions and adsorption mechanisms in more detail. Every day, developments in computers and computational software are made to increase the computational power to study more complex systems. In this thesis, computational methods were used to study the reactivity of two classes of compounds and their interaction with carbon-based materials; the two classes are platinum-based antitumor drugs and fluoroquinolones antimicrobials compounds. The hydrolysis reaction of cis-[Pt(PMe3)2(etga)], cis-[Pt(PMe3)2(3-Hfl)]+ containing ethyl gallate (etga) and 3-Hydroxyflavone(3-HFl), designed to try to limit the side effects of cisplatin, studied by means of density functional theory (DFT) calculations. The calculations showed that the activation energies are significantly lower than those calculated for cisplatin, with consequent high hydrolysis reaction rate that might make such complexes subject to fast degradation, causing potentially poor pharmacological activity; indeed, the complexes present lower cytotoxic activity compared to cisplatin. The complete mechanism of action (hydrolysis reaction, reaction with DNA bases and reaction with cysteine) of phenanthriplatin, a monofunctional platinum complex, was studied by means of DFT calculations. Moreover, a comparison between phenanthriplatin and cisplatin was made with the aim of understanding why phenanthriplatin presents a higher cytotoxicity activity compared to cisplatin. The hydrolysis reaction showed that phenanthriplatin\u2019s activation energy barrier is close to the energy barriers obtained for the first hydrolysis of cisplatin. The reaction with guanine is kinetically favoured in phenanthriplatin in respect to cisplatin. Finally, the reaction between phenanthriplatin and cysteine showed that such reaction is disadvantageous, both kinetically and thermodynamically, in phenanthriplatin in respect to cisplatin. This can explain why phenanthriplatin is more cytotoxic than cisplatin. The non-covalent interaction between graphene prototypes, new candidates as drugs delivery systems, and cisplatin were investigated through MP2 and DFT calculation. Different orientations of cisplatin in respect to the circumcoronene, one parallel and three perpendicular, were taken into account. The parallel orientation presents the highest value of interaction energy in vacuum. Finally, the introduction of the solvent does not drastically change the interaction energy profiles between cisplatin and circumcoronene. Thus, a favourable adsorption of cisplatin on graphene can be predicted. As regards the fluoroquinolones (FQ) antimicrobials compounds, the relative stability and photochemical behaviour of the different protonation states of CFX in gas phase and in water was studied by means of molecular dynamics simulations and DFT calculations. This work confirm the predominance of the zwitterionic form in water in respect to the neutral form. Finally, the protonation sequence was confirmed through the comparison with the crystalline structures found in the literature, through the calculation of the relative stability for such species and the calculated absorption UV-Vis spectra. Finally, the adsorption of both neutral and zwitterionic forms of CFX to the inner and outer surface of carbon nano-tubes (CNT) in vacuum and in water was studied through molecular dynamics simulations. The simulation results showed that CFX remains adsorbed to the surface of CNT both in vacuum and in water thanks to p-p interactions. Finally, the adsorption Gibbs free energy were carried out for the adsorbed zCFX and nCFX, finding out that adsorption is thermodynamically favoured. In conclusion, the use of computational chemistry can help to rationalize the experimental data and to investigate various mechanicistic hypothesis

Computational Study of Compounds with Biological Activity and their Interaction with Nano-Materials

In the last few decades, computer simulation became a potent tool to study experimental systems such as chemical reactions and adsorption mechanisms in more detail. Every day, developments in computers and computational software are made to increase the computational power to study more complex systems. In this thesis, computational methods were used to study the reactivity of two classes of compounds and their interaction with carbon-based materials; the two classes are platinum-based antitumor drugs and fluoroquinolones antimicrobials compounds. The hydrolysis reaction of cis-[Pt(PMe3)2(etga)], cis-[Pt(PMe3)2(3-Hfl)]+ containing ethyl gallate (etga) and 3-Hydroxyflavone(3-HFl), designed to try to limit the side effects of cisplatin, studied by means of density functional theory (DFT) calculations. The calculations showed that the activation energies are significantly lower than those calculated for cisplatin, with consequent high hydrolysis reaction rate that might make such complexes subject to fast degradation, causing potentially poor pharmacological activity; indeed, the complexes present lower cytotoxic activity compared to cisplatin. The complete mechanism of action (hydrolysis reaction, reaction with DNA bases and reaction with cysteine) of phenanthriplatin, a monofunctional platinum complex, was studied by means of DFT calculations. Moreover, a comparison between phenanthriplatin and cisplatin was made with the aim of understanding why phenanthriplatin presents a higher cytotoxicity activity compared to cisplatin. The hydrolysis reaction showed that phenanthriplatin\u2019s activation energy barrier is close to the energy barriers obtained for the first hydrolysis of cisplatin. The reaction with guanine is kinetically favoured in phenanthriplatin in respect to cisplatin. Finally, the reaction between phenanthriplatin and cysteine showed that such reaction is disadvantageous, both kinetically and thermodynamically, in phenanthriplatin in respect to cisplatin. This can explain why phenanthriplatin is more cytotoxic than cisplatin. The non-covalent interaction between graphene prototypes, new candidates as drugs delivery systems, and cisplatin were investigated through MP2 and DFT calculation. Different orientations of cisplatin in respect to the circumcoronene, one parallel and three perpendicular, were taken into account. The parallel orientation presents the highest value of interaction energy in vacuum. Finally, the introduction of the solvent does not drastically change the interaction energy profiles between cisplatin and circumcoronene. Thus, a favourable adsorption of cisplatin on graphene can be predicted. As regards the fluoroquinolones (FQ) antimicrobials compounds, the relative stability and photochemical behaviour of the different protonation states of CFX in gas phase and in water was studied by means of molecular dynamics simulations and DFT calculations. This work confirm the predominance of the zwitterionic form in water in respect to the neutral form. Finally, the protonation sequence was confirmed through the comparison with the crystalline structures found in the literature, through the calculation of the relative stability for such species and the calculated absorption UV-Vis spectra. Finally, the adsorption of both neutral and zwitterionic forms of CFX to the inner and outer surface of carbon nano-tubes (CNT) in vacuum and in water was studied through molecular dynamics simulations. The simulation results showed that CFX remains adsorbed to the surface of CNT both in vacuum and in water thanks to p-p interactions. Finally, the adsorption Gibbs free energy were carried out for the adsorbed zCFX and nCFX, finding out that adsorption is thermodynamically favoured. In conclusion, the use of computational chemistry can help to rationalize the experimental data and to investigate various mechanicistic hypothesis

Molecular interpretation of pharmaceuticals' adsorption on carbon nanomaterials: Theory meets experiments

The ability of carbon-based nanomaterials (CNM) to interact with a variety of pharmaceutical drugs can be exploited in many applications. In particular, they have been studied both as carriers for in vivo drug delivery and as sorbents for the treatment of water polluted by pharmaceuticals. In recent years, the large number of experimental studies was also assisted by computational work as a tool to provide understanding at molecular level of structural and thermodynamic aspects of adsorption processes. Quantum mechanical methods, especially based on density functional theory (DFT) and classical molecular dynamics (MD) simulations were mainly applied to study adsorption/release of various drugs. This review aims to compare results obtained by theory and experiments, focusing on the adsorption of three classes of compounds: (i) simple organic model molecules; (ii) antimicrobials; (iii) cytostatics. Generally, a good agreement between experimental data (e.g. energies of adsorption, spectroscopic properties, adsorption isotherms, type of interactions, emerged from this review) and theoretical results can be reached, provided that a selection of the correct level of theory is performed. Computational studies are shown to be a valuable tool for investigating such systems and ultimately provide useful insights to guide CNMs materials development and design

Using Theory to Reinterpret the Kinetics of Monofunctional Platinum Anticancer Drugs: Stacking Matters

The monofunctional platinum drug phenanthriplatin (phenPt) blocks the replication of cancer cells even if it reacts with only one guanine base. However, there is still insufficient experimental data to improve its cytotoxicity and all previously proposed chemical modifications of the parent structure have resulted in a loss of activity. We use theoretical tools to illustrate the key steps in the biological mechanisms of phenPt; that is, its activation in water and the subsequent attack on DNA. Our simulations suggest that the measured kinetic parameters, which are based on free nucleobases in solution, need to be reinterpreted because the self-assembled stacked reactive adduct formed in the reaction is inaccessible in real DNA. The constants reported here will help guide future work in the synthesis of anticancer platinum drugs

Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells

The chiral cationic complex [Ru(η1-OAc)(CO)((R,R)-Skewphos)(phen)]OAc (2R), isolated from reaction of [Ru(η1-OAc)(η2-OAc)(R,R)-Skewphos)(CO)] (1R) with phen, reacts with NaOPiv and KSAc affording [RuX(CO)((R,R)-Skewphos)(phen)]Y (X=Y=OPiv 3R; X=SAc, Y=OAc 4R). The corresponding enantiomers 2S-4S have been obtained from 1S containing (S,S)-Skewphos. Reaction of 2R and 2S with (S)-cysteine and NaPF6 at pH=9 gives the diastereoisomers [Ru((S)-Cys)(CO)(PP)(phen)]PF6 (PP=(R,R)-Skewphos 2R-Cys; (S,S)-Skewphos 2S-Cys). The DFT energetic profile for 2R with (S)-cysteine in H2O indicates that aquo and hydroxo species are involved in formation of 2R-Cys. The stability of the ruthenium complexes in 0.9 % w/v NaCl solution, PBS and complete DMEM medium, as well as their n-octanol/water partition coefficient (logP), have been evaluated. The chiral complexes show high cytotoxic activity against SW1736, 8505 C, HCT-116 and A549 cell lines with EC50 values of 2.8–0.04 μM. The (R,R)-Skewphos derivatives show higher cytotoxicity compared to their enantiomers, 4R (EC50=0.04 μM) being 14 times more cytotoxic than 4S against the anaplastic thyroid cancer 8505 C cell line

The Complex Story Behind a Deep Eutectic Solvent Formation as Revealed by L‑Menthol Mixtures with Butylated Hydroxytoluene Derivatives.

An in-depth study of the hydrophobic eutectic mixtures formed by L-menthol (MEN) with the butylated hydroxytoluene (BHT), 2-tert-butyl-pcresol (TBC), and p-cresol (PC) compounds has been carried out, where TBC and PC are analogous to the BHT species but with a different degree of steric hindrance around the hydroxyl group. Thermal characterization evidenced that the BHT/MEN system can be classified as an ideal eutectic, while the TBC/MEN and PC/MEN mixtures behave as type V deep eutectic solvents (DESs) for a wide range of compositions around the eutectic point. As shown by an array of experimental and theoretical methods, in the BHT/MEN mixtures the establishment of hydrogen-bond (H-bond) interactions between the components is dramatically hampered because of the steric hindrance in the BHT molecule, so that the achievement of a liquid phase at room temperature for the eutectic composition is driven by apolar−apolar attractions among the alkyl functional groups of the constituents. Differently, the TBC-MEN donor−receptor H-bond is the main driving force for the formation of a type V DES and derives from a concurrence of electronic and steric factors characterizing the TBC molecule. Finally, the absence of steric hindrance around the hydroxyl group allows the self-association among PC molecules through H-bonded networks already in the pristine compound, but the replacement with the more favorable PC-MEN H-bond provides a type V DES upon mixing of these components. Our combined approach, together with the peculiarity of the inspected systems, delivered an archetypal study able to shed light onto the various contributions ruling the structure− properties relationship in DESs and possibly deepening the currently accepted view of these inherently complex media

Fuori di casa : l’edilizia residenziale pubblica in Veneto dopo la legge regionale n. 39/2017

I centri storici italiani vedono da anni allargarsi un fronte civico accomunato dalla volontà di contrastare il turismo di massa, e dall’altro dalla richiesta di nuove politiche per la residenza, e in particola e per la casa. Storicamente al centro delle politiche di welfare, alle quali fa ecco a sua volta l’SDG 11 Città e comunità sostenibili, l’edilizia residenziale pubblica appare del resto minacciata su più fronti. Questo contributo, frutto dell’esperienza maturata dall’Osservatorio civico sulla casa e sulla residenza (Ocio) di Venezia, intende confrontare il quadro normativo e istituzionale per l’edilizia residenziale pubblica in Veneto con il contesto sociale del suo capoluogo. A pochi mesi dall’entrata in vigore della nuova legge regionale (n. 39/2017), la sua applicazione sta suscitando forti tensioni, in un ambito peraltro già fragile. Il contributo si propone in un primo momento di analizzare la normativa regionale veneta e di metterne in luce le principali caratteristiche. Si tratterà poi di anticipare il potenziale impatto di una sua piena applicazione nel caso di Venezia, facendo riferimento anche alle diverse iniziative cittadine già in atto per contrastarla. Sarà quindi possibile proporre una lettura critica delle politiche per la casa in essere in Veneto