Ruthenium complexes bearing nile red chromophore and one of its derivative: Theoretical evaluation of PDT-related properties.

The outcomes of DFT-based calculations are here reported to assess the applicability of two synthesized polypyridyl Ru(II) complexes, bearing ethynyl nile red (NR) on a bpy ligand, and two analogues, bearing modified-NR, in photodynamic therapy. The absorption spectra, together with the non-radiative rate constants for the S1 - Tn intersystem crossing transitions, have been computed for this purpose. Calculations evidence that the structural modification on the chromophore destabilizes the HOMO of the complexes thus reducing the H-L gap and, consequently, red shifting the maximum absorption wavelength within the therapeutic window, up to 620 nm. Moreover, the favored ISC process from the bright state involves the triplet state closest in energy, which is also characterized by the highest SOC value and by the involvement of the whole bpy ligand bearing the chromophore in delocalising the unpaired electrons. These outcomes show that the photophysical behavior of the complexes is dominated by the chromophore.

Computational assessment of the use of graphene-based nanosheets as PtII chemotherapeutics delivery systems.

Graphene is the newest form of elemental carbon and it is becoming rapidly a potential candidate in the framework of nano-bio research. Many reports confirm the successful use of graphene-based materials as carriers of anticancer drugs having relatively high loading capacities compared with other nanocarriers. Here, the outcomes of a systematic study of the adsorption behavior of FDA approved PtII drugs cisplatin, oxaliplatin, and carboplatin on surface models of pristine, holey, and nitrogen-doped holey graphene are reported. DFT investigations in water solvent have been carried out considering several initial orientations of the drugs with respect to the surfaces. Adsorption free energies, calculated including basis set superposition error (BSSE) corrections, result to be significantly negative for many of the drug@carrier adducts indicating that tested layers could be used as potential carriers for the delivery of anticancer PtII drugs. The reduced density gradient (RDG) analysis allows to show that many kinds of non-covalent interactions, including canonical H-bond, are responsible for the stabilization of the formed adducts.

A detailed density functional theory exploration of the photodissociation mechanism of ruthenium complexes for photoactivated chemotherapy.

Polypyridyl Ru(II) complexes have attracted much attention due to their potential as light-activatable anticancer agents in photoactivated chemotherapy (PACT). The action of ruthenium-based PACT compounds relies on the breaking of a coordination bond between the metal center and an organic ligand via a photosubstitution reaction. Here, a detailed computational investigation of the photophysical properties of a novel trisheteroleptic ruthenium complex, [Ru(dpp)(bpy)(mtmp)]2+ (dpp = 4,7-diphenyl-1,10-phenanthroline, bpy = 2,2'-bipyridine and mtmp = 2-methylthiomethylpyridine), has been carried out by means of DFT and its time-dependent extension. All the aspects of the mechanism by which, upon light irradiation, the mtmp protecting group is released and the corresponding aquated complex, able to bind to DNA inducing cell death, is formed have been explored in detail. All the involved singlet and triplet states have been fully described, providing the calculation of the corresponding energy barriers. The involvement of solvent molecules in photosubstitution and the role played by pyridyl-thioether chelates as caging groups have been elucidated.

Cytotoxic Pt(II) complexes containing alizarin: a selective carrier for DNA metalation.

Many efforts have been made in the last few decades to selectively transport antitumor agents to their potential target sites with the aim to improve efficacy and selectivity. Indeed, this aspect could greatly improve the beneficial effects of a specific anticancer agent especially in the case of orphan tumors like the triple negative breast cancer. A possible strategy relies on utilizing a protective leaving group like alizarin as the Pt(II) ligand to reduce the deactivation processes of the pharmacophore enacted by Pt resistant cancer cells. In this study a new series of neutral mixed-ligand Pt(II) complexes bearing alizarin and a variety of diamine ligands were synthesized and spectroscopically characterized by FT-IR, NMR and UV-Vis analyses. Three Pt(II) compounds, i.e., 2b, 6b and 7b, emerging as different both in terms of structural properties and cytotoxic effects (not effective, 10.49 ± 1.21 µM and 24.5 ± 1.5 µM, respectively), were chosen for a deeper investigation of the ability of alizarin to work as a selective carrier. The study comprises the in vitro cytotoxicity evaluation against triple negative breast cancer cell lines and ESI-MS interaction studies relative to the reaction of the selected Pt(II) complexes with model proteins and DNA fragments, mimicking potential biological targets. The results allow us to suggest the use of complex 6b as a prospective anticancer agent worthy of further investigations.

Observation of Long-Lived Charge-Separated States in Anthraquinone-Phenothiazine Electron Donor-Acceptor Dyads: Transient Optical and Electron Paramagnetic Resonance Spectroscopic Studies.

We prepared a series of phenothiazine (PTZ)-anthraquinone (AQ) electron donor-acceptor dyads to study the relationship between molecular structures and the possibility of charge transfer (CT) and intersystem crossing (ISC). As compared to the previously reported PTZ-AQ dyad with a direct connection of two units via a C-N single bond, the PTZ and AQ units are connected via a p-phenylene or p-biphenylene linker. Conformation restriction is imposed by attaching ortho-methyl groups on the phenylene linker. UV-vis absorption spectra indicate electronic coupling between the PTZ and AQ units in the dyads without conformation restriction. Different from the previously reported PTZ-AQ, thermally activated delayed fluorescence (TADF) is observed for the dyads containing one phenylene linker (PTZ-Ph-AQ and PTZ-PhMe-AQ). The prompt fluorescence lifetime in cyclohexane is exceptionally long (τPF = 62.0 ns, population ratio: 99.2%) and 245.0 ns (93.5%) for PTZ-Ph-AQ and PTZ-PhMe-AQ, respectively (normally τPF <20 ns); the delayed fluorescence lifetimes for these two dyads were determined as τDF = 2.4 µs (6.5%) and 7.6 µs (0.8%), respectively. For the dyad containing a biphenylene linker (PTZ-Ph2Me-AQ), no TADF was observed. Charge-separated (CS) states were observed for PTZ-Ph-AQ and PTZ-PhMe-AQ, and the lifetimes were determined as 7.0 and 1.3 µs, respectively, indicating the triplet spin multiplicity of the CS state. The 3CS state lifetimes are shortened to 100 ns and 440 ns for the two dyads, respectively, in the polar solvent acetonitrile. For dyads with a longer linker, i.e., PTZ-Ph2Me-AQ, the CS state lifetime is not sensitive to solvent polarity (τCS = 1.8 and 1.3 µs in cyclohexane and acetonitrile, respectively). In reference dyads, where the PTZ unit is oxidized to sulfoxide, no CT absorption band and TADF were observed, which is attributed to the increased CS state energy (>3 eV) becoming higher than that of the AQ triplet (3AQ*) state (ca. 2.7 eV). These experimental evidence show that the presence of 1CS, 3CS, and 3LE (LE: locally excited) states sharing similar energy is essential for the occurrence of TADF. Population of the long-lived 3CS state (with a lifetime of a few µs) does not produce by itself TADF, because the ISC process of 1CS→3CS is nonsufficient. Femtosecond transient absorption spectra show that charge separation (CS) occurs readily (<5 ps) for most dyads, even in nonpolar solvents. Nanosecond pulsed laser-excited time-resolved electron paramagnetic resonance (TREPR) spectra show that either a spin correlated radical pair (SCRP) is formed, with the electron exchange energy 2J = +2.14 mT, or radical pairs with stronger interaction, |2J| > 6.57 mT. These studies are useful for in-depth understanding of the CS and ISC in compact electron donor-acceptor dyads and for design of efficient TADF emitters.

The current status in computational exploration of Pt(IV) prodrug activation by reduction.

Octahedral PtIV complexes are considered highly promising candidates for overcoming some shortcomings of clinically approved PtII drugs. PtIV compounds, owing to their inertia, appear to be capable of resisting premature aquation and undesired binding to essential plasma proteins and have shown remarkable potential for both oral administration and for reducing side effects. Additionally, their pharmacological properties can be finely tuned by choosing appropriate axial ligands. The reduction inside the cell by biological reducing agents to the correponding active cytotoxic PtII species, accompanied by the loss of the axial ligands, is considered an essential step of their mechanism and has been extensively studied. However, a detailed understanding of the mechanism by which PtIV prodrugs are activated, which should be highly beneficial for their proper design, is lacking, and many contradictory results continue to be collected. In the hope of contributing to the advancement of knowledge in this field, this perspective focuses on the insights gained from computational studies carried out with the aim of finding answers to the many still open questions concerning the reduction of PtIV complexes in biological environments.

Computational Assessment of a Dual-Action Ru(II)-Based Complex: Photosensitizer in Photodynamic Therapy and Intercalating Agent for Inducing DNA Damage.

A combined quantum-mechanical and classical molecular dynamics study of a recent Ru(II) complex with potential dual anticancer action is reported here. The main basis for the multiple action relies on the merocyanine ligand, whose electronic structure allows the drug to be able to absorb within the therapeutic window and in turn efficiently generate 1O2 for photodynamic therapy application and to intercalate within two nucleobases couples establishing reversible electrostatic interactions with DNA. TDDFT outcomes, which include the absorption spectrum, triplet states energy, and spin-orbit matrix elements, evidence that the photosensitizing activity is ensured by an MLCT state at around 660 nm, involving the merocyanine-based ligand, and by an efficient ISC from such state to triplet states with different characters. On the other hand, the MD exploration of all the possible intercalation sites within the dodecamer B-DNA evidences the ability of the complex to establish several electrostatic interactions with the nucleobases, thus potentially inducing DNA damage, though the simulation of the absorption spectra for models extracted by each MD trajectory shows that the photosensitizing properties of the complex remain unaltered. The computational results support that the anti-tumor effect may be related to multiple mechanisms of action.

Does Twisted Molecular Structure Always Induce Intersystem Crossing? A Case Study with Near-IR Absorbing 1,8-Diazabicyclo[5.4.0]undec-7-ene-fused Naphthaldiimide.

Heavy atom-free organic chromophores showing absorption in the near-IR region with intersystem crossing (ISC) ability are important for applications in various fields, e.g., photocatalysis and photodynamic therapy. Herein, we studied the photophysical property of a naphthalenediimide (NDI) derivative, in which the NDI chromophore is fused with pentacyclic 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), which shows a strong charge-transfer (CT) absorption band (S0 → 1CT transition) in the near-IR region of 600-740 nm. The effect of extended π-conjugation framework in NDI-DBU compared with the derivative of mono-amino substitution (NDI-NH-Br) was studied by steady-state and nanosecond transient absorption (ns-TA) spectra, electron paramagnetic resonance (EPR) spectroscopy, and theoretical computations. The fluorescence is almost completely quenched for NDI-DBU (ΦF = 1.0%) as compared with NDI-NH-Br (ΦF = 24% in toluene). However, the ISC of NDI-DBU is poor, and the singlet oxygen quantum yield was determined as ΦΔ = 9% versus ΦΔ = 57% for NDI-NH-Br, although the compound has significantly twisted molecular structure. The ns-TA spectral study showed a long-lived triplet excited state (τT = 132 µs) in NDI-DBU, with T1 energy of 1.20-1.44 eV, and the ISC is via the S2 → T3 path, which is verified by theoretical calculations. This study displayed that the twisting of molecular geometry does not always assure efficient ISC.

Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)-Salphen Complex.

Aiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal-containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B-DNA. G-quadruplex nucleic acid, obtained by self-assembly of guanine-rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design. Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)-salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G-quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner- and outer-sphere mechanisms, and the active Pt(II) complex, as a function of its protonation state, stabilizes the G-quadruplex DNA prevalently, either establishing π-stacking interactions with the terminal G-tetrad or through electrostatic interactions along with H-bonds formation.

Riboflavin-Promoted In Situ Photoactivation of Dihydroalkaloid Prodrugs for Cancer Therapy.

Cancer therapies usually suffer from poor targeting ability and serious side effects. Photoactivatable cancer therapy has the significant advantage of a high spatiotemporal resolution, but most photoactivatable prodrugs require decoration with stoichiometric photocleavable groups, which are only responsive to ultraviolet irradiation and suffer from low reaction efficiency. To tackle these challenges, we herein propose a photoactivation strategy with biogenic riboflavin as the photosensitizer to promote the in situ transformation of noncytotoxic dihydroalkaloid prodrugs dihydrochelerythrine (DHCHE), dihydrosanguinarine (DHSAN), and dihydronitidine (DHNIT) into anticancer alkaloid drugs chelerythrine (CHE), sanguinarine (SAN), and nitidine (NIT), respectively, which can efficiently kill cancer cells and inhibit in vivo tumor growth. Meanwhile, the photoactivatable transformation can be in situ monitored by green-to-red fluorescence conversion, which will contribute to easy controlling of the therapeutic dose. The proposed photoactivatable transformation mechanism was also explored by density functional theory (DFT) calculations. We believe this riboflavin-promoted and imaging-guided photoactivation strategy is promising for precise cancer therapy.

Curcumin-based ionic Pt(II) complexes: antioxidant and antimicrobial activity.

A series of novel cationic curcumin-based Pt(II) complexes with neutral (N^N) ligands and triflate anions as counterions, [(N^N)Pt(curc)]CF3SO3, 1-4, were synthesised and fully characterised. The antioxidant radical scavenging activity of complexes 1-4 was measured spectrophotometrically using DPPH as the internal probe. Computational strategies have been exploited to ascertain the mechanism of antioxidant action of curcumin (H(curc)) and its Pt(II) complexes. Finally, compounds 1-4 were tested in vitro for their growth inhibitory activity against two bacteria (Staphylococcus aureus and Escherichia coli) by the disk diffusion technique at different Pt(II) complex solution concentrations. The effect of the complexation of H(curc) was investigated.

Computational Analysis of the Behavior of BODIPY Decorated Monofunctional Platinum(II) Complexes in the Dark and under Light Irradiation.

Dual-action drugs are occupying an important place in the scientific landscape of cancer research owing to the possibility to combine different therapeutic strategies into a single molecule. In the present work, the behavior of two BODIPY-appended monofunctional Pt(II) complexes, one mononuclear and one binuclear, recently synthesized and tested for their cytotoxicity have been explored both in the dark and under light irradiation. Quantum mechanical DFT calculations have been used to carry out the exploration of the key steps, aquation and guanine attack, of the mechanism of action of Pt(II) complexes in the dark. Due to the presence of the BODIPY chromophore and the potential capability of the two investigated complexes to work as photosensitizers in PDT, time dependent DFT has been employed to calculate their photophysical properties and to inspect how the sensitizing properties of BODIPY are affected by the presence of the platinum "heavy atom". Furthermore, also the eventual influence on of the photophysical properties due to the displacement of chlorido ligands by water and of water by guanine has been taken into consideration.

How Computations Can Assist the Rational Design of Drugs for Photodynamic Therapy: Photosensitizing Activity Assessment of a Ru(II)-BODIPY Assembly.

Ruthenium-based complexes represent a new frontier in light-mediated therapeutic strategies against cancer. Here, a density functional-theory-based computational investigation, of the photophysical properties of a conjugate BODIPY-Ru(II) complex, is presented. Such a complex was reported to be a good photosensitizer for photodynamic therapy (PDT), successfully integrating the qualities of a NIR-absorbing distyryl-BODIPY dye and a PDT-active [Ru(bpy)3]2+ moiety. Therefore, the behaviour of the conjugate BODIPY-Ru(II) complex was compared with those of the metal-free BODIPY chromophore and the Ru(II) complex. Absorptions spectra, excitation energies of both singlet and triplet states as well as spin-orbit-matrix elements (SOCs) were used to rationalise the experimentally observed different activities of the three potential chromophores. The outcomes evidence a limited participation of the Ru moiety in the ISC processes that justifies the small SOCs obtained for the conjugate. A plausible explanation was provided combining the computational results with the experimental evidences.

On the origin of photodynamic activity of hypericin and its iodine-containing derivatives.

The main photophysical properties, useful for establishing whether hypericin in anionic form and some of its derivatives containing heavy atoms such as iodine, can be proposed for their use in photodynamic therapy, were determined using density functional based computations. The results showed that in the anionic form and in the iodinated derivatives, the absorption wavelength undergoes a bathochromic shift, the singlet-triplet energy gap assumes values ​that allow to excite the oxygen molecule from its ground to the excited singlet state, and that the spin-orbit couplings between singlet and triplet states significantly increase.

Computational Exploration of the Synergistic Anticancer Effect of a Multi-Action Ru(II)-Pt(IV) Conjugate.

An in-depth computational study of the ability of a recently proposed multi-action Ru(II)-Pt(IV) conjugate to act as a photosensitizer in photodynamic therapy (PDT) and chemotherapeutic drugs is presented here. The investigated complex is characterized by a polypyridyl Ru(II) chromophore linked to a Pt(IV) complex that, acting as a prodrug, should be activated by reduction releasing the Ru-based chromophore that can absorb light of proper wavelength to be used in PDT. The reaction mechanism for active species formation has been fully elucidated by means of density functional theory and its time-dependent extension. The reduction mechanism, assisted by ascorbate, of the Pt(IV) prodrug to the Pt(II) active species has been explored, taking into consideration all the possible modes of attack of the reductant for releasing the axial ligands and affording active cisplatin. Given the similarity in the photophysical properties of the chromophore linked or not to the Pt(IV) complex, both the Ru(II)-Pt(IV) conjugate precursor and the Ru(II) chromophore should be able to act as PDT photosensitizers according to type I and type II photoprocesses. In particular, they are able to generate singlet oxygen cytotoxic species as well as auto-ionize to form highly reactive O2-• species.

Porphyrins and Metalloporphyrins Combined with N-Heterocyclic Carbene (NHC) Gold(I) Complexes for Photodynamic Therapy Application: What Is the Weight of the Heavy Atom Effect?

The photophysical properties of two classes of porphyrins and metalloporphyrins linked to N-heterocyclic carbene (NHC) Au(I) complexes have been investigated by means of density functional theory and its time-dependent extension for their potential application in photodynamic therapy. For this purpose, the absorption spectra, the singlet-triplet energy gaps, and the spin-orbit coupling (SOC) constants have been determined. The obtained results show that all the studied compounds possess the appropriate properties to generate cytotoxic singlet molecular oxygen, and consequently, they can be employed as photosensitizers in photodynamic therapy. Nevertheless, on the basis of the computed SOCs and the analysis of the metal contribution to the involved molecular orbitals, a different influence in terms of the heavy atom effect in promoting the intersystem crossing process has been found as a function of the identity of the metal center and its position in the center of the porphyrin core or linked to the peripheral NHC.

Cytotoxicity of Alizarine versus Tetrabromocathecol Cyclometalated Pt(II) Theranostic Agents: A Combined Experimental and Computational Investigation.

Platinum compounds cytotoxicity is strictly related to their ability to be converted into active mono- and di-aquated species and consequently to the replacement of labile ligands by water molecules. This activation process makes the platinum center prone to nucleophilic substitution by DNA purines. In the present work, quantum mechanical density functional theory (DFT) computations and experimental investigations were carried out in order to shed light on the relationship between the internalization, aquation, and DNA binding of two isostructural anionic theranostic complexes previously reported by our group, NBu4[(PhPy)Pt(Aliz)], 1 (IC50 1.9 ± 1.6 µM), and NBu4[(PhPy)Pt(BrCat)], 2 (IC50 52.8 ± 3.9 µM). Cisplatin and a neutral compound [(NH3)2Pt(Aliz)], 3, were also taken as reference compounds. The computed energy barriers and the endergonicity of the hydrolysis reactions showed that the aquation rates are comparable for 1 and 2, with a slightly higher reactivity of 1. The second hydrolysis process was proved to be the rate-determining step for both 1 and 2, unlike for compound 3. The nucleophilic attack by the N7 site of guanine to both mono- and di-aquated forms of the complexes was computationally investigated as well, allowing to rationalize the observed different cytotoxicity. Computational results were supported by photostability data and biological assays, demonstrating DNA as the main target for compound 1.

Activation by Glutathione in Hypoxic Environment of an Azo-based Rhodamine Activatable Photosensitizer. A Computational Elucidation.

In the present paper, density functional theory (DFT) has been applied to the study of the activation mechanism of a new selenium azo-rhodamine (azoSeRho) in presence of the tripeptide thiol, glutathione (GSH), as potent activatable photosensitizer to be employed in photodynamic therapy. The introduction of the azo group into the conjugated system of the seleno-rhodamine dye and its reaction with GSH allow the selective formation of the active photosensitizer, SeRho. Furthermore, DFT calculations have allowed to shed light on the activation mechanism of the azoSeRho photosensitizer when molecular oxygen is present and hydrogen peroxide is formed. This study is the first theoretical investigation revealing how the reductive cleavage of the azo moiety by GSH occurs. Time-dependent DFT approach has been used to evaluate the chalcogen-substitution effect on the structures and photophysical properties of the azo derivatives and, then, on the activated photosensitizers.

Computational Analysis of Photophysical Properties and Reactivity of a New Phototherapeutic Cyclometalated Au(III)-Hydride Complex.

Gold(III) complexes have recently emerged as new versatile and efficacious metal containing anticancer agents. In an attempt to reconcile the specific affinity of such complexes for target sulfur containing biomolecules with their capability to strongly bind thiol-containing compounds widely distributed in non-tumoral cells, a new series of cyclometalated Au(III)-hydride complexes has been proposed as photoactivatable anticancer prodrugs. Here, the computational exploration of the photophysical properties and reactivity in dark and under light irradiation of the first member of the series, named 1 a, is reported. Complex 1 a low hydricity in dark together with facile hydride substitution leading to H2 elimination under excitation by visible light have been examined by means of DFT and TD-DFT computations. Both singlet and triplet excited states have been characterized, allowing the identification of the active species involved in photoactivation pathways leading to the controlled detachment of the hydride ligand. Also the viable two-photon activation at the ideal phototherapeutic window has been investigated.

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.