Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study.

The oxazaphosphorine cyclophosphamide (CP) is a DNA-alkylating agent commonly used in cancer chemotherapy. This anticancer agent is administered as a prodrug activated by a liver cytochrome P450-catalyzed 4-hydroxylation reaction that yields the active, cytotoxic metabolite. The primary metabolite, 4-hydroxycyclophosphamide, equilibrates with the ring-open aldophosphamide that undergoes ß-elimination to yield the therapeutically active DNA cross-linking phosphoramide mustard and the byproduct acrolein. The present paper presents a DFT investigation of the different metabolic phases and an insight into the mechanism by which CP exerts its cytotoxic action. A detailed computational analysis of the energy profiles describing all the involved transformations and the mechanism of DNA alkylation is given with the aim to contribute to an increase of knowledge that, after more than 60 years of unsuccessful attempts, can lead to the design and development of a new generation of oxazaphosphorines.

Hole interactions of aerogen oxides with Lewis bases: an insight into σ-hole and lone-pair-hole interactions.

σ-Hole and lone-pair (lp)-hole interactions of aerogen oxides with Lewis bases (LB) were comparatively inspected in terms of quantum mechanics calculations. The ZOn ⋯ LB complexes (where Z = Kr and Xe, n = 1, 2, 3 and 4, and LB = NH3 and NCH) showed favourable negative interaction energies. The complexation features were explained in light of σ-hole and lp-hole interactions within optimum distances lower than the sum of the respective van der Waals radii. The emerging findings outlined that σ-hole interaction energies generally enhanced according to the following order: KrO4 ⋯ < KrO⋯ < KrO3⋯ < KrO2⋯LB and XeO4⋯ < XeO⋯ < XeO2⋯ < XeO3⋯LB complexes with values ranging from -2.23 to -12.84 kcal mol-1. Lp-hole interactions with values up to -5.91 kcal mol-1 were shown. Symmetry-adapted perturbation theory findings revealed the significant contributions of electrostatic forces accounting for 50-65% of the total attractive forces within most of the ZOn⋯LB complexes. The obtained observations would be useful for the understanding of hole interactions, particularly for the aerogen oxides, with application in supramolecular chemistry and crystal engineering.

Preferability of Molnupiravir, an Anti-COVID-19 Drug, toward Purine Nucleosides: A Quantum Mechanical Study.

Structural aspects of molnupiravir complexed with the RNA of the SARS-CoV-2 virus have been recently resolved inside the RNA-dependent RNA polymerase (RdRp), demonstrating the interactions of molnupiravir with purine nucleosides. However, the preference of molnupiravir to interact with one purine nucleoside over another has not been clearly investigated. Herein, the complexation of molnupiravir in its active form with guanosine and adenosine was compared, using sundry density functional theory calculations. The plausible tautomeric structures of the molnupiravir drug in complex with guanosine/adenosine were minutely scrutinized. The relative energy findings outlined the favorability of amino-molnupiravir···keto-amino-guanosine and imino-molnupiravir···amino-adenosine optimized complexes. According to the interaction (Eint) and binding (Ebind) energy values, higher preferential base-pairing of molnupiravir with guanosine over the adenosine one was recognized with Eint/Ebind values of -31.16/-21.81 and -13.93/-12.83 kcal/mol, respectively. This could be interpreted by the presence of three and two hydrogen bonds within the former and latter complexes, respectively. Observable changes in the electronic properties and global indices of reactivity of the studied complexes also confirmed the preferential binding within the studied complexes. The findings from the quantum theory of atoms in molecules and the noncovalent interaction index also support the partially covalent nature of the investigated interactions. For both complexes, changes in thermodynamic parameters outlined the spontaneous, exothermic, and nonrandom states of the inspected interactions. Inspecting the solvent effect on the studied interactions outlined more observable amelioration within the water medium compared with the gas one. These results would be a durable ground for the forthcoming studies concerned with the interactions of the molnupiravir drug with purine nucleosides.

Elucidating the adsorption of 2-Mercaptopyridine drug on the aluminum phosphide (Al12P12) nanocage: A DFT study.

Adsorption amplitude of the aluminum phosphide (Al12P12) nanocage toward the 2-Mercaptopyridine (MCP) drug was herein monitored based on density functional theory (DFT) calculations. The adsorption process through MCP⋅⋅⋅Al12P12 complex in various configurations was elucidated by means of adsorption (Eads) energies. According to the energetic affirmations, the Al12P12 nanocage demonstrated potential versatility toward adsorbing the MCP drug within the investigated configurations and exhibited significant negative adsorption energies up to -27.71 kcal/mol. Upon the results of SAPT analysis, the electrostatic forces showed the highest contributions to the overall adsorption process with energetic values up to -74.36 kcal/mol. Concurrently, variations of molecular orbitals distribution along with alterations in the energy gap (Egap) and Fermi level (EFL) of the studied nanocage were denoted after adsorbing the MCP drug. The favorable impact of water solvent within the MCP⋅⋅⋅Al12P12 complexes was unveiled and confirmed by negative solvation energy (ΔEsolv) values up to -17.75 kcal/mol. According to thermodynamic parameters, the spontaneous and exothermic natures of the considered adsorption process were proclaimed by negative values of ΔG and ΔH parameters. Significant changes in the IR and Raman peaks, along with the appearance of new peaks, were noticed, confirming the occurrence of the targeted adsorption process. Furthermore, the adsorption features of the MCP drug on the Al12N12 nanocage were elucidated and compared to the Al12P12 analog. The obtained results demonstrated the higher preferability of Al12P12 nanocage than the Al12N12 candidate towards adsorbing the MCP drug without structural distortion.

A green compliant hand-held selective electrode device for monitoring active pharmaceuticals and the kinetics of their degradation.

An in-line smartphone connected to a screen-printed selective electrode hand-held device was used to determine the concentration of distigmine bromide (DB) in its pure and dosage forms as well as its degradation kinetics by continuously measuring the change in the produced emf over time. The main objective, supported by the data presented, is to produce a highly reliable smartphone integrated selective sensor as a portable analyzer with potential high cloud connectivity combining a wide linear dynamic range, the fastest response time with the lowest limits of detection and quantitation while best integrating green analytical chemistry principles. The choice of ionophore used in this approach was guided by computation and the data obtained was compared with traditional analytical techniques. DB, for which there are no previously reported stability-indicating methods and for which four novel such methods are proposed here, was selected as a model drug for this work. At-line UV-spectrophotometry DB assay was obtained by measuring the difference between the spectra of the degradation product and the same concentration of intact drug. The degradation kinetics were studied by this method through tracking the decrease of DB absorbance and/or the increase of a generated degradation product signal over time. Off-line separation based HPLC and TLC stability-indicating methods for DB were also presented. All methods employed in this work were validated for accuracy, precision, specificity, repeatability, linearity, range, detection and quantification limits according to the ICH guidelines and were applied to the analysis of laboratory prepared mixtures as well as commercial products. While all methods proposed were shown to be highly reliable, the smartphone integrated selective sensor is highlighted as a portable analyzer with potential high cloud connectivity and was shown to combine a wide linear dynamic range, the fastest response time with the lowest limits of detection and quantitation while best integrating green analytical chemistry principles.

Adsorption Features of Tetrahalomethanes (CX4; X = F, Cl, and Br) on ß12 Borophene and Pristine Graphene Nanosheets: A Comparative DFT Study.

The potentiality of the ß12 borophene (ß12) and pristine graphene (GN) nanosheets to adsorb tetrahalomethanes (CX4; X = F, Cl, and Br) were investigated using density functional theory (DFT) methods. To provide a thorough understanding of the adsorption process, tetrel (XC-X3∙∙∙ß12/GN)- and halogen (X3C-X∙∙∙ß12/GN)-oriented configurations were characterized at various adsorption sites. According to the energetic manifestations, the adsorption process of the CX4∙∙∙ß12/GN complexes within the tetrel-oriented configuration led to more desirable negative adsorption energy (Eads) values than that within the halogen-oriented analogs. Numerically, Eads values of the CBr4∙∙∙Br1@ß12 and T@GN complexes within tetrel-/halogen-oriented configurations were -12.33/-8.91 and -10.03/-6.00 kcal/mol, respectively. Frontier molecular orbital (FMO) results exhibited changes in the EHOMO, ELUMO, and Egap values of the pure ß12 and GN nanosheets following the adsorption of CX4 molecules. Bader charge transfer findings outlined the electron-donating property for the CX4 molecules after adsorbing on the ß12 and GN nanosheets within the two modeled configurations, except the adsorbed CBr4 molecule on the GN sheet within the tetrel-oriented configuration. Following the adsorption process, new bands and peaks were observed in the band structure and density of state (DOS) plots, respectively, with a larger number in the case of the tetrel-oriented configuration than in the halogen-oriented one. According to the solvent effect affirmations, adsorption energies of the CX4∙∙∙ß12/GN complexes increased in the presence of a water medium. The results of this study will serve as a focal point for experimentalists to better comprehend the adsorption behavior of ß12 and GN nanosheets toward small toxic molecules.

In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study.

Multidrug resistance (MDR) is one of the most problematic issues in chemotherapeutic carcinoma therapy. The ABCB1 transporter, a drug efflux pump overexpressed in cancer cells, has been thoroughly investigated for its association with MDR. Thus, discovering ABCB1 inhibitors can reverse the MDR in cancer cells. In the current work, a molecular docking technique was utilized for hunting the most prospective ABCB1 inhibitors from the Toxin and Toxin-Target Database (T3DB). Based on the docking computations, the most promising T3DB compounds complexed with the ABCB1 transporter were subjected to molecular dynamics (MD) simulations over 100 ns. Utilizing the MM-GBSA approach, the corresponding binding affinities were computed. Compared to ZQU (calc. -49.8 kcal/mol), Emamectin B1a (T3D1043), Emamectin B1b (T3D1044), Vincristine (T3D4016), Vinblastine (T3D4017), and Vindesine (T3D2479) complexed with ABCB1 transporter demonstrated outstanding binding affinities with ΔGbinding values of -93.0, -92.6, -93.8, -92.2, and -90.8 kcal/mol, respectively. The structural and energetic investigations confirmed the constancy of the identified T3DB compounds complexed with the ABCB1 transporter during the 100 ns MD course. To mimic the physiological conditions, MD simulations were conducted for those identified inhibitors complexed with ABCB1 transporter in the presence of a POPC membrane. These findings revealed that Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse the MDR. Therefore, subjecting those compounds to further in-vitro and in-vivo investigations is worthwhile.

Adsorption of Favipiravir on pristine graphene nanosheets as a drug delivery system: a DFT study.

The efficiency of pristine graphene (GN) in the delivery process of the Favipiravir (FPV) anti-COVID-19 drug was herein revealed within the FPV⋯GN complexes in perpendicular and parallel configurations in terms of the density functional theory (DFT) method. Adsorption energy findings unveiled that the parallel configuration of FPV⋯GN complexes showed higher desirability than the perpendicular one, giving adsorption energy up to -15.95 kcal mol-1. This favorability could be interpreted as a consequence of the contribution of π-π stacking to the overall strength of the adsorption process in the parallel configuration. Frontier molecular orbitals (FMO) findings demonstrated the ability of the GN nanosheet to adsorb the FPV drug by the alteration in the EHOMO, ELUMO, and Egap values before and after the adsorption process. Based on Bader charge results, the FPV drug and GN sheet exhibited electron-donating and -accepting characters, respectively, which was confirmed by the negative sign of the computed charge transfer (Qt) values. The FPV(R)⋯T@GN complex showed the most desirable Qt value of -0.0377e, which was in synoptic with the adsorption energy pattern. Electronic properties of GN were also altered after the adsorption of the FPV drug in both configurations, with more observable changes in the parallel one. Interestingly, the Dirac point of the GN sheet coincided with the Fermi level after the adsorption process, indicating that the adsorption process unaffected the presence of the Dirac point. The occurrence of the adsorption process was also noticed by the existence of new bands and peaks in the band structure and DOS plots, respectively. Short recovery time rendered the GN nanosheet an efficient FPV drug delivery system. The obtained findings provide new insight into the biomedical applications of the GN sheet as a promising drug delivery system.

On the Use of Graphene Nanosheets for Drug Delivery: A Case Study of Cisplatin and Some of Its Analogs.

Graphene (GN) nanosheets have been widely exploited in biomedical applications as potential nanocarriers for various drugs due to their distinct physical and chemical properties. In this regard, the adsorption behavior of cisplatin (cisPtCl2) and some of its analogs on a GN nanosheet was investigated in perpendicular and parallel configurations by using density functional theory (DFT). According to the findings, the most significant negative adsorption energies (Eads) within the cisPtX2⋯GN complexes (where X = Cl, Br, and I) were observed for the parallel configuration, with values up to -25.67 kcal/mol at the H@GN site. Within the perpendicular configuration of the cisPtX2⋯GN complexes, three orientations were investigated for the adsorption process, namely, X/X, X/NH3, and NH3/NH3. The negative Eads values of the cisPtX2⋯GN complexes increased with the increasing atomic weight of the halogen atom. The Br@GN site showed the largest negative Eads values for the cisPtX2⋯GN complexes in the perpendicular configuration. The Bader charge transfer outcomes highlighted the electron-accepting properties of cisPtI2 within the cisPtI2⋯GN complexes in both configurations. The electron-donating character of the GN nanosheet increased as the electronegativity of the halogen atom increased. The band structure and density of state plots revealed the occurrence of the physical adsorption of the cisPtX2 on the GN nanosheet, which was indicated by the appearance of new bands and peaks. Based on the solvent effect outlines, the negative Eads values generally decreased after the adsorption process in a water medium. The recovery time results were in line with the Eads findings, where the cisPtI2 in the parallel configuration took the longest time to be desorbed from the GN nanosheet with values of 61.6 × 108 ms at 298.15 K. The findings of this study provide better insights into the utilization of GN nanosheets in drug delivery applications.

Anti-Cancer Peptides: Status and Future Prospects.

The dramatic rise in cancer incidence, alongside treatment deficiencies, has elevated cancer to the second-leading cause of death globally. The increasing morbidity and mortality of this disease can be traced back to a number of causes, including treatment-related side effects, drug resistance, inadequate curative treatment and tumor relapse. Recently, anti-cancer bioactive peptides (ACPs) have emerged as a potential therapeutic choice within the pharmaceutical arsenal due to their high penetration, specificity and fewer side effects. In this contribution, we present a general overview of the literature concerning the conformational structures, modes of action and membrane interaction mechanisms of ACPs, as well as provide recent examples of their successful employment as targeting ligands in cancer treatment. The use of ACPs as a diagnostic tool is summarized, and their advantages in these applications are highlighted. This review expounds on the main approaches for peptide synthesis along with their reconstruction and modification needed to enhance their therapeutic effect. Computational approaches that could predict therapeutic efficacy and suggest ACP candidates for experimental studies are discussed. Future research prospects in this rapidly expanding area are also offered.

Analysis of the Fragmentation Pathways for the Collision-Induced Dissociation of Protonated Cyclophosphamide: A Mass Spectrometry and Quantum Mechanical Study.

Cyclophosphamide is a well-known anticancer agent acting by means of DNA alkylation. Associated with its tumor selectivity, it also possesses a wide spectrum of toxicities. As the requirement of metabolic activation before cyclophosphamide exerts either its therapeutic or toxic effects is well recognized, research aiming at elucidating the pathways that lead to the activation of this drug is of key importance. This has created the necessity for developing an effective analytical method for detecting cyclophosphamide and its breakdown products. In this paper, an Acquity TQ tandem quadrupole mass spectrometer equipped with electrospray ionization in positive-ion mode was employed for detecting cyclophosphamide in its protonated form. The full-scan mass spectrum of cyclophosphamide shows two ion clusters displaying the characteristic isotopic pattern of two chlorine atoms and assigned as sodiated cyclophosphamide, [CP + Na]+, and protonated cyclophosphamide, [CP + H]+ or PCP. With the aid of quantum mechanical DFT calculation, free energy differences in the gas phase among PCP protomers were computed with respect to the most stable protomer being protonated on the 2-oxide oxygen of the 1,3,2-oxazaphosphorine-2-oxide ring. In addition, the interconversion mechanisms among the different protomers were also proposed by intercepting the corresponding transition states in the gas phase. Collision-induced dissociation (CID) of PCP generated six characteristic product ions. Fragmentation mechanisms were proposed and supported by computation. The calculated energy barriers for all of the located transition states were found to be accessible under the reported experimental conditions.

Flavin-mediated photoactivation of Pt(IV) anticancer complexes: computational insights on the catalytic mechanism.

The mechanism for the photocatalytic activation of Pt(IV) anticancer prodrugs by riboflavin in the presence of NADH has been investigated by DFT. In the first step of the reaction, the oxidation kinetics of NADH to afford the catalytically active riboflavin hydroquinone is dramatically favoured by generation of the flavin triplet excited state. In the triplet, formation of a π-π stacked adduct promotes the hydride transfer from NADH to riboflavin with an almost barrierless pathway (2.7 kcal mol-1). In the singlet channel, conversely, the process is endergonic and requires overcoming a higher activation energy (19.2 kcal mol-1). In the second half of the reaction, the reduction of the studied Pt(IV) complexes by riboflavin hydroquinone occurs via an inner sphere mechanism, displaying free energy barriers smaller than 10 kcal mol-1. Pt reduction by bioreductants such as NADH and ascorbate involve instead less stabilized transition states (22.2-38.3 kcal mol-1), suggesting that riboflavin hydroquinone is an efficient reducing agent for Pt(IV) derivatives in biological settings.

A Boron-Containing Compound Acting on Multiple Targets Against Alzheimer's Disease. Insights from Ab Initio and Molecular Dynamics Simulations.

Given the multifactorial nature and pathogenesis of Alzheimer's disease, therapeutic strategies are addressed to combine the benefits of every single-target drug into a sole molecule. Quantum mechanics and molecular dynamics (MD) methods were employed here to investigate the multitarget action of a boron-containing compound against Alzheimer's disease. The antioxidant activity as a radical scavenger and metal chelator was explored by means of density functional theory. The most plausible radical scavenger mechanisms, which are hydrogen transfer, radical adduct formation, and single-electron transfer in aqueous and lipid environments, were fully examined. Metal chelation ability was investigated by considering the complexation of Cu(II) ion, one of the metals that in excess can even catalyze the ß-amyloid (Aß) aggregation. The most probable complexes in the physiological environment were identified by considering both the stabilization energy and the shift of the λmax induced by the complexation. The excellent capability to counteract Aß aggregation was explored by performing MD simulations on protein-ligand adducts, and the activity was compared with that of curcumin, chosen as a reference.

Anticancer Activity, DNA Binding, and Photodynamic Properties of a N∧C∧N-Coordinated Pt(II) Complex.

In the effort to discover new targets and improve the therapeutic efficacy of metal-containing anticancer compounds, transition metal complexes that can elicit cytotoxicity when irradiated with light of a proper wavelength and, then, candidates as potential photosensitizers for photodynamic therapy are actively being investigated. In this work, the cytotoxicity in the dark and the photophysical properties of the complex Pt(N∧C∧N)Cl, where the N∧C∧N ligand is 2,6-dipyrido-4-methyl-benzene chloride, are investigated in detail by means of a series of theoretical levels, that is density functional theory and its time-dependent extension together with molecular dynamics (MD) simulations. In the dark, cytotoxicity has been explored by simulating the steps of the mechanism of action of classical Pt(II) complexes. The suitability of the investigated complex to act as a photosensitizer has been verified by calculating spectroscopic properties for both the unperturbed complex and its aquated and guanine-bound forms. Furthermore, using MD simulation outcomes as a starting point, the photophysical properties of DNA-intercalated and -bound complexes have been evaluated with the goal of establishing how intercalation and binding affect sensitization activity.

Is the cytotoxic activity of phenanthriplatin dependent on the specific size of the phenanthridine ligand π system?

The monofunctional Pt(II) drug phenanthriplatin is a leading preclinical anticancer drug, whose main characteristic is the presence of the extended aromatic system of the phenanthridine ligand, which allows intercalation. Intercalation, in turn, induces DNA unwinding and facilitates DNA binding. Aiming at verifying to what extent the peculiar cytotoxic activity of phenanthriplatin depends on the specific size of the aromatic system, two phenanthriplatin derivatives have been designed increasing the number of the rings in the N-heterocyclic ligand, and their reactivity has been computationally investigated. Both quantum mechanical DFT computations and molecular dynamics (MD) simulations have been employed to investigate some of the aspects that are considered important for the activity of Pt(II) monofunctional complexes. In particular, the substitution of the chlorido ligand with water, subsequent interaction of the aquated complexes with guanine as a model, eventual deactivation by the model N-acetyl methionine as well as intercalation into, binding to and distortion of DNA have been examined. The outcomes of such analysis have been compared with the analogous ones for the phenanthriplatin complex in order to highlight how the addition of one more ring to the phenanthridine ligand and, eventually, its identity influence the reactivity and, consequently, the cytotoxic profile of the complexes.

Iodido equatorial ligands influence on the mechanism of action of Pt(IV) and Pt(II) anti-cancer complexes: A DFT computational study.

A detailed computational exploration of the most relevant steps of iodido Pt(IV) complexes reduction and Pt(II) drugs mechanism of action and eventual deactivation is presented here inspired by the recent findings on iodido Pt(II) complexes and surprising re-evaluation of their cytotoxic activity. Pt(II) and Pt(IV) model systems are investigated and compared with cisplatin and its Pt(IV) derivative. Both monodeprotonated ascorbic acid and l-cysteine are used as reducing agents in the inner-sphere reduction mechanism of Pt(IV) complexes. Aquation mechanism of iodido Pt(II) complexes, interaction with guanine and sulfur containing compounds and reaction with the model protein hen egg white lysozyme are explored, due to a detected different behavior with respect to classical platinum drugs. The outcomes of such exploration allow to shed light on the role that the increased soft character together with bridging and leaving abilities of iodide over chloride could play in determining the cytotoxic profile of iodido Pt drugs.

A multi-methodological inquiry of the behavior of cisplatin-based Pt(IV) derivatives in the presence of bioreductants with a focus on the isolated encounter complexes.

The study of Pt(IV) antitumor prodrugs able to circumvent some drawbacks of the conventional Pt(II) chemotherapeutics is the focus of a lot of attention. This paper reports a thorough study based on experimental methods (reduction kinetics, electrochemistry, tandem mass spectrometry and IR ion spectroscopy) and quantum-mechanical DFT calculations on the reduction mechanism of cisplatin-based Pt(IV) derivatives having two hydroxido (1), one hydroxido and one acetato (2), or two acetato ligands (3) in axial position. The biological reductants glutathione and ascorbic acid were taken into consideration. The presence of a hydroxido ligand resulted to play an important role in the chemical reduction with ascorbic acid, as verified by 15N-NMR kinetic analysis using 15N-enriched complexes. The reactivity trend (1 > 2 > 3) does not reflect the respective reduction peak potentials (1 < 2 < 3), an inverse relationship already documented in similar systems. Turning to a simplified environment, the Pt(IV) complexes associated with a single reductant molecule (corresponding to the encounter complex occurring along the reaction coordinate in bimolecular reactions in solution) were characterized by IR ion spectroscopy and sampled for their reactivity under collision-induced dissociation (CID) conditions. The complexes display a comparable reduction reactivity ordering as that observed in solution. DFT calculations of the free energy pathways for the observed fragmentation reactions provide theoretical support for the CID patterns and the mechanistic hypotheses on the reduction process are corroborated by the observed reaction paths. The bulk of these data offers a clue of the intricate pathways occurring in solution.Graphic abstract.

Rationalization of the Superior Anticancer Activity of Phenanthriplatin: An In-Depth Computational Exploration.

In the effort to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents, a large number of cisplatin variants continues today to be prepared and tested. One of the applied strategies is to use monofunctional platinum complexes that, unlike traditional bifunctional compounds, are able to form only a single covalent bond with nuclear DNA. Chirality, aquation reaction, interaction with guanine and N-acetyl methionine as well as, intercalation into, binding to and distortion of DNA have been investigated by using both quantum mechanical DFT and molecular dynamics computations aiming at contributing to the elucidation of the molecular mechanism underlying the significantly enhanced spectrum of activity of the monofunctional PtII drug phenanthriplatin. Analogous calculations have been performed in parallel for other two less potent monofunctional PtII drugs, pyriplatin and enpyriplatin, which show very different cytotoxic effects.

Antitumor Platinium(IV) Prodrugs: A Systematic Computational Exploration of Their Reduction Mechanism by l-Ascorbic Acid.

The reduction mechanism of Pt(IV) anticancer prodrugs, still today a matter of debate, assisted by one of the dominant reductants in human plasma, that is l-ascorbic acid in its monodeprotonated form, has been computationally examined in this work. In order to check what should be the influence on the reduction rate of the identity of the ligands in axial and equatorial position, both cisplatin and oxaliplatin derivatives have been studied, varying the ligands in axial position in connection with the role they should play as bridges, trans leaving species, and proton acceptors. OH, OAc, Cl, and Br ligands have been tested as bridging/leaving ligands, whereas Cl and aspirin have been used as trans labile and less labile ligands, respectively. The most recent theoretical and experimental investigations have demonstrated that the generally adopted grouping of reduction mechanisms into inner- and outer-sphere does not properly take into account all the viable alternatives. Therefore, inner-sphere mechanisms, classified as ligand-bridged, ligand-bridged-H transfer and enolate ß-carbon attack, have been explored for all the complexes under investigation. Concerning the outer-sphere mechanism, redox potentials have been calculated adopting a recently proposed procedure based on the separation between electrochemical and chemical events to evaluate their propensity to be reduced. Moreover, according to the hypothesis that the outer-sphere reduction mechanism involves the sequential addition of two electrons causing the formation of a Pt(III) intermediate, the possibility that singlet and triplet pathways can cross for the Pt(IV) cisplatin derivative having two chlorido ligands in axial position has been explored in detail. Results show that the mechanism indicated as base-assisted outer sphere can become competitive with respect to the inner one if two singlet-triplet spin inversions occur. Results presented here are helpful in addressing synthetic strategies as they show that Pt(IV) prodrugs propensity to be reduced can be properly tuned and give indications on how this aim can be accomplished.