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The hyphenation of HPLC with its high separation ability and ICP-MS with its excellent sensitivity, allows the analysis of Pt drugs in biological samples at the low nanomolar concentration levels. On the other hand, LC-MS provides molecular structural confirmation for each species. Using a combination of these methods, we have investigated the speciation of the photoactive anticancer complex diazido Pt(IV) complex trans, trans, trans-[Pt(N3)2(OH)2(py)2] (FM-190) in aqueous solution and biofluids at single-digit nanomolar concentrations before and after irradiation. FM-190 displays high stability in human blood plasma in the dark at 37 °C. Interestingly, the polyhydroxido species [{PtIV(py)2(OH)4} + Na]+ and [{PtIV(py)2(N3)(OH)3} + Na]+ resulting from the replacement of azido ligands, as determined by LC-MS, were the major products after photoirradiation of FM-190 with blue light (463 nm). This finding suggests that such photosubstituted Pt(IV) tri- and tetra-hydroxido species could play important roles in the biological activity of this anticancer complex. Density Functional Theory (DFT) and Time-Dependent DFT (TDDFT) calculations show that these Pt(IV) species arising from FM-190 in aqueous media can be formed directly from a singlet excited state. The results highlight how speciation analysis (metallomics) can shed light on photoactivation pathways for FM-190 and formation of potential excited-state pharmacophores. The ability to detect and identify photoproducts at physiologically-relevant concentrations in cells and tissues will be important for preclinical development studies of this class of photoactivatable platinum drugs.
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Antineoplásicos , Oxidación-Reducción , Procesos Fotoquímicos , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/síntesis química , Luz , Azidas/química , Platino (Metal)/química , Estructura Molecular , Complejos de Coordinación/química , Complejos de Coordinación/síntesis químicaRESUMEN
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.
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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.
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Antineoplásicos , Cisplatino , Teoría Funcional de la Densidad , Portadores de Fármacos , Grafito , Grafito/química , Antineoplásicos/química , Cisplatino/química , Portadores de Fármacos/química , Carboplatino/química , Nanoestructuras/química , Oxaliplatino/química , Sistemas de Liberación de Medicamentos , Adsorción , Compuestos Organoplatinos/químicaRESUMEN
The novel hetero-dinuclear complex trans,trans,trans-[PtIV(py)2(N3)2(OH)(µ-OOCCH2CH2CONHCH2-bpyMe)IrIII(ppy)2]Cl (Pt-Ir), exhibits charge transfer between the acceptor photochemotherapeutic Pt(IV) (Pt-OH) and donor photodynamic Ir(III) (Ir-NH2) fragments. It is stable in the dark, but undergoes photodecomposition more rapidly than the Pt(IV) parent complex (Pt-OH) to generate Pt(II) species, an azidyl radical and 1O2. The Ir(III)* excited state, formed after irradiation, can oxidise NADH to NADâ radicals and NAD+. Pt-Ir is highly photocytotoxic towards cancer cells with a high photocytotoxicity index upon irradiation with blue light (465â nm, 4.8â mW/cm2), even with short light-exposure times (10-60â min). In contrast, the mononuclear Pt-OH and Ir-NH2 subunits and their simple mixture are much less potent. Cellular Pt accumulation was higher for Pt-Ir compared to Pt-OH. Irradiation of Pt-Ir in cancer cells damages nuclei and releases chromosomes. Synchrotron-XRF revealed ca. 4× higher levels of intracellular platinum compared to iridium in Pt-Ir treated cells under dark conditions. Luminescent Pt-Ir distributes over the whole cell and generates ROS and 1O2 within 1â h of irradiation. Iridium localises strongly in small compartments, suggestive of complex cleavage and excretion via recycling vesicles (e.g. lysosomes). The combination of PDT and PACT motifs in one molecule, provides Pt-Ir with a novel strategy for multimodal phototherapy.
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Antineoplásicos , Iridio , Fotoquimioterapia , Fármacos Fotosensibilizantes , Platino (Metal) , Iridio/química , Iridio/farmacología , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Platino (Metal)/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Estructura Molecular , Supervivencia Celular/efectos de los fármacosRESUMEN
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.
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Photoactive prodrugs offer potential for spatially-selective antitumour activity with minimal effects on normal tissues. Excited-state chemistry can induce novel effects on biochemical pathways and combat resistance to conventional drugs. Photoactive metal complexes in particular, have a rich and relatively unexplored photochemistry, especially an ability to undergo facile intersystem crossing and populate triplet states. We have conjugated the photoactive octahedral Pt(iv) complex trans, trans, trans-[Pt(N3)2(OH)2(py)2] to ferrocene to introduce novel features into a candidate photochemotherapeutic drug. The X-ray crystal structure of the conjugate Pt-Fe confirmed the axial coordination of a ferrocene carboxylate, with Pt(iv) and Fe(ii) 6.07 Å apart. The conjugation of ferrocene red-shifted the absorption spectrum and ferrocene behaves as a light antenna allowing charge transfer from iron to platinum, promoting the photoactivation of Pt-Fe with light of longer wavelength. Cancer cellular accumulation is enhanced, and generation of reactive species is catalysed after photoirradiation, introducing ferroptosis as a contribution towards the cell-death mechanism. TDDFT calculations were performed to shed light on the behaviour of Pt-Fe when it is irradiated. Intersystem spin-crossing allows the formation of triplet states centred on both metal atoms. The dissociative nature of triplet states confirms that they can be involved in ligand detachment due to irradiation. The Pt(ii) photoproducts mainly retain the trans-{Pt(py)2}2+fragment. Visible light irradiation gives rise to micromolar activity for Pt-Fe towards ovarian, lung, prostate and bladder cancer cells under both normoxia and hypoxia, and some photoproducts appear to retain Pt(iv)-Fe(ii) conjugation.
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Targeting of G-quadruplex (G-Q) nucleic acids, which are helical four-stranded structures formed from guanine-rich nucleic acid sequences, has emerged in recent years as an appealing opportunity for drug intervention in anticancer therapy. Small-molecule drugs can stabilize quadruplex structures, promoting selective downregulation of gene expression and telomerase inhibition and also activating DNA damage responses. Thus, rational design of small molecular ligands able to selectively interact with and stabilize G-Q structures is a promising strategy for developing potent anti-cancer drugs with selective toxicity towards cancer cells over normal ones. Here, the outcomes of a thorough computational investigation of a recently synthesized monofunctional PtII complex (Pt1), whose selectivity for G-Q is activated by what is called adaptive binding, are reported. Quantum mechanics and molecular dynamics calculations have been employed for studying the classical key steps of the mechanism of action of PtII complexes, the conversion of the non-charged and non-planar Pt1 complex into a planar and charged PtII (Pt2) complex able to play the role of a G-Q binder and, finally, the interaction of Pt2 with G-Q. The information obtained from such an investigation allows us to rationalize the behavior of the novel PtII complex proposed to be activated by adaptive binding toward selective interaction with G-Q or similar molecules and can be exploited for designing ligands with more effective recognition ability toward G-quadruplex DNA.
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Antineoplásicos , G-Cuádruplex , ADN/química , Antineoplásicos/farmacología , Antineoplásicos/química , Secuencia de Bases , LigandosRESUMEN
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.
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Antineoplásicos , Profármacos , Profármacos/farmacología , Profármacos/química , Profármacos/metabolismo , Ligandos , Antineoplásicos/química , Sustancias Reductoras , Línea Celular TumoralRESUMEN
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.
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Fotoquimioterapia , Rutenio , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Sustancias Intercalantes/farmacología , Sustancias Intercalantes/química , Ligandos , Daño del ADN , Rutenio/farmacología , Rutenio/químicaRESUMEN
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.
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Antiinfecciosos , Complejos de Coordinación , Curcumina , Curcumina/farmacología , Curcumina/química , Antioxidantes/farmacología , Antioxidantes/química , Complejos de Coordinación/química , Bacterias , Antiinfecciosos/farmacología , Antiinfecciosos/químicaRESUMEN
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.
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Fármacos Fotosensibilizantes , Platino (Metal) , Compuestos de Boro , Guanina , Ligandos , Compuestos Organoplatinos/farmacología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/efectos de la radiación , AguaRESUMEN
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.
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Fotoquimioterapia , Rutenio , Compuestos de Boro , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
Para-sulfocalix[n]arenes are promising host molecules that can accommodate various chemotherapeutic drugs. Pt(IV)-based complexes, including satraplatin and asplatin, are promising alternatives that overcome the shortcomings of Pt(II) complexes. In this study, asplatin has been synthesized by fusing acetylsalicylic acid (aspirin) and cisplatin. Furthermore, it has been characterized using 1H NMR, mass spectrometry, elemental analysis, and UHPLC. A host-guest complex of asplatin and p-sulfocalix[4]arene (PSC4) has been developed and characterized using UV, Job's plot analysis, HPLC, and density functional theory (DFT) calculations. The experimental and computational investigations propose that a 1:1 complex between asplatin and PSC4 is formed. The stability constant of the designed complex has been determined using Job's plot and UHPLC and computed to be 9.1 × 104 M-1 and 8.7 × 104 M-1, which corresponds to a free energy of complexation of -6.8 kcal mol-1, while the calculated value for the inclusion free energy is -13.2 kcal mol-1. Both experimentally and theoretically estimated complexation free energy show that a stable host-guest complex can be formed in solution. The in vitro drug release study displayed the ability of the complex to release its cargo at a cancerous pH (pH of 5.5). Additionally, the asplatin/PSC4 complex is shown to be biocompatible when tested on human skin fibroblast noncancerous cells, demonstrating the highest in vitro cytotoxic activity against (MCF-7), cervical (HeLa), and lung cancer cells (A-549), with IC50 values of 0.75, 2.15, and 3.60 µg/mL, respectively. This is as compared to either cisplatin (IC50 of 5.47, 5.94 and 9.61 µg/mL, respectively) or asplatin (IC50 of 1.54, 5.05 and 3.91 µg/mL, respectively). On the other hand, the free asplatin exhibited higher cytotoxicity on cancerous cells and lower toxicity on noncancerous cells. The outcomes of the present joint theoretical and experimental investigation reinforce the interest in platinum-based anticancer therapeutics when they are protected from undesired interactions and suggest the use of the PSC4 macromolecule as a promising carrier for Pt(IV) anticancer drugs. The formed asplatin/PSC4 inclusion complex may represent an effective chemotherapeutic agent.
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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.
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Fotoquimioterapia , Fármacos Fotosensibilizantes , Glutatión/química , Humanos , Hipoxia , Fármacos Fotosensibilizantes/química , Rodaminas/químicaRESUMEN
p-Sulfonatocalix[n]arenes have shown excellent potential for accommodating chemotherapeutic drugs through host-guest complexation and enhancing their anticancer activity. Betaine has been reported to exert an anticancer effect at high concentrations. In order to increase its concentration in cancer cells, we have complexed it with p-SC4, which releases its content in an acidic environment typical of cancer tissue. In this work, a host-guest complex of the chemically stable, natural, and safe active methyl donor (betaine) and p-sulfonatocalix[4]arenes (p-SC4) was designed and characterized using 1H NMR, UV, Job's plot analysis, DFT calculations, and molecular modeling for use in cancer therapeutics. The peak amplitude of the prepared host-guest complexes was linearly proportional to the concentration of betaine in the range of 1.0 × 10-5 M-1 to 2.5 × 10-4 M-1. The reaction stoichiometry between p-SC4 and betaine in the formed complex was 1 : 1. The stability constant for the complex is 8.9 × 104 M-1 which corresponds to a complexation free energy of -6.74 kcal mol-1. Complexation between betaine and p-SC4 was found to involve the insertion of the trimethylammonium group of betaine into the p-SC4 cavity, as supported by the experimental data. The complex displayed enhanced cytotoxic activities against breast adenocarcinoma cells (MCF-7) and cervical cancer cells (HeLa) compared to free betaine. In conclusion, the host-guest complexation of betaine with p-SC4 increases its concentration in cancer cells, which warrants further investigation for cancer therapy.
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P-sulfonatocalix[n]arenes have demonstrated a great potential for encapsulation of therapeutic drugs via host-guest complexation to improve solubility, stability, and bioavailability of encapsulated drugs. In this work, guest-host complexes of a third-generation anticancer drug (oxaliplatin) and p-4-sulfocalix[n]arenes (n = 4 and 6; p-SC4 and p-SC6, respectively) were prepared and investigated, using 1H NMR, UV, Job's plot analysis, and DFT calculations, for use as cancer therapeutics. The peak amplitude of the prepared host-guest complexes was linearly proportional to the concentration of oxaliplatin in the range of 1.0 × 10-5 M-1 to 2.1 × 10-4 M-1. The reaction stoichiometry between either p-SC4 or p-SC6 and oxaliplatin in the formed complexes was 1:1. The stability constants for the complexes were 5.07 × 104 M-1 and 6.3 × 104 M-1. These correspond to complexation free energy of -6.39 and -6.52 kcal/mol for p-SC4 and p-SC6, respectively. Complexation between oxaliplatin and p-SC4 or p-SC6 was found to involve hydrogen bonds. Both complexes exhibited enhanced biological and high cytotoxic activities against HT-29 colorectal cells and MCF-7 breast adenocarcinoma compared to free oxaliplatin, which warrants further investigation for cancer therapy.
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Antineoplásicos/síntesis química , Arilsulfonatos/síntesis química , Calixarenos/síntesis química , Composición de Medicamentos/métodos , Oxaliplatino/farmacología , Antineoplásicos/metabolismo , Arilsulfonatos/metabolismo , Calixarenos/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HT29 , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Cinética , Células MCF-7 , Modelos Químicos , Oxaliplatino/metabolismo , Teoría Cuántica , TermodinámicaRESUMEN
Supramolecular systems (macromolecules), such as calix[n]arenes (SCn), cyclodextrins (CDs), and cucurbiturils (CBs), are promising vehicles for anticancer drugs. In this work, guest-host complexes of carboplatin, a second-generation platinum-based anticancer drug, and p-4-sulfocalix[n]arenes (n = 4 and 6; PS4 and PS6, respectively) were prepared and studied using 1H NMR, UV, Job's plot analysis, HPLC, and density-functional theory calculations. The experimental and the computational studies suggest the formation of 1:1 complexes between carboplatin and each of PS4 and PS6. The stability constants of the formed complexes were estimated to be 5.3 × 104 M-1 and 9.8 × 104 M-1, which correspond to free energy of complexation of -6.40 and -6.81 kcal mol-1, in the case of PS4 and PS6, respectively. The interaction free energy depends on the different inclusion modes of carboplatin in the host cavities. UV-vis findings and atoms in molecules analysis showed that hydrogen bond interactions stabilize the host-guest complexes without the full inclusion in the host cavity. The in vitro anticancer study revealed that both complexes exhibited stronger anticancer activities against breast adenocarcinoma cells (MCF-7) and lung cancer cells (A-549) compared to free carboplatin, preluding to their potential use in cancer therapy.
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Enhanced sampling molecular dynamics has been used to model the reduction mechanism of the antitumoral Asplatin Pt(IV) complex, c,c,t-[PtCl2(NH3)2(OH)(aspirin)] in the presence of l-ascorbic acid as reducing agent. In order to overcome the timescale problem, characteristic of many chemical reactions, we enhanced the sampling of the free energy landscape using Metadynamics. To achieve such a goal, the selection of adequate collective variables is crucial for the application of the method. Recently, a new method called Multi-Class Harmonic Linear Discriminant Analysis (MC-HLDA) has been proposed as a tool for constructing collective variables (CVs) for complex chemical processes. The method reduces the dimensionality of the variable space by generating appropriate linear combinations of several relevant chemical descriptors. The aim of this work is to assess the ability and performance of this method in describing the fundamental features of complex chemical reactions such as the Asplatin reduction mechanism in a compact, simple, and physically transparent manner. © 2019 Wiley Periodicals, Inc.
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Aspirina/química , Compuestos Organoplatinos/química , Profármacos/química , Análisis Discriminante , Simulación de Dinámica Molecular , Oxidación-ReducciónRESUMEN
Organometallic complexes with novel activation mechanisms are attractive anticancer drug candidates. Here, we show that half-sandwich iodido cyclopentadienyl iridium(iii) azopyridine complexes exhibit potent antiproliferative activity towards cancer cells, in most cases more potent than cisplatin. Despite their inertness towards aquation, these iodido complexes can undergo redox activation by attack of the abundant intracellular tripeptide glutathione (GSH) on the chelated azopyridine ligand to generate paramagnetic intermediates, and hydroxyl radicals, together with thiolate-bridged dinuclear iridium complexes, and liberate reduced hydrazopyridine ligand. DFT calculations provided insight into the mechanism of this activation. GS- attack on the azo bond facilitates the substitution of iodide by GS-, and leads to formation of GSSG and superoxide if O2 is present as an electron-acceptor, in a largely exergonic pathway. Reactions of these iodido complexes with GSH generate Ir-SG complexes, which are catalysts for GSH oxidation. The complexes promoted elevated levels of reactive oxygen species (ROS) in human lung cancer cells. This remarkable ligand-centred activation mechanism coupled to redox reactions adds a new dimension to the design of organoiridium anticancer prodrugs.
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In contrast to the clinical drug cisplatin, the anticancer complex [Os(η6-p-cymene)(4-(2-pyridylazo)-N,N-dimethylaniline)I]+ [1-I] is inert towards hydrolysis and targets cancer cell metabolism rather than DNA. A combination of DFT calculations and X-ray absorption spectroscopy (XAS) suggests that hydrolytic activation of 1-I involves catalytic attack by the intracellular tripeptide glutathione (GSH) on the azo bond of the chelating ligand in the complex.