Nanodrugs based on co-delivery strategies to combat cisplatin resistance.

Cisplatin (CDDP), as a broad-spectrum anticancer drug, is able to bind to DNA and inhibit cell division. Despite the widespread use of cisplatin since its discovery, cisplatin resistance developed during prolonged chemotherapy, similar to other small molecule chemotherapeutic agents, severely limits its clinical application. Cisplatin resistance in cancer cells is mainly caused by three reasons: DNA repair, decreased cisplatin uptake/increased efflux, and cisplatin inactivation. In earlier combination therapies, the emergence of multidrug resistance (MDR) in cancer cells prevented the achievement of the desired therapeutic effect even with the accurate combination of two chemotherapeutic drugs. Therefore, combination therapy using nanocarriers for co-delivery of drugs is considered to be ideal for alleviating cisplatin resistance and reducing cisplatin-related toxicity in cancer cells. This article provides an overview of the design of cisplatin nano-drugs used to combat cancer cell resistance, elucidates the mechanisms of action of cisplatin and the pathways through which cancer cells develop resistance, and finally discusses the design of drugs and related carriers that can synergistically reduce cancer resistance when combined with cisplatin.

Boost the Circularly Polarized Phosphorescence of Chiral Organometallic Platinum Complexes by Hierarchical Assembly into Fibrillar Networks.

Circularly polarized luminescence (CPL)-active molecular materials have drawn increasing attention due to their promising applications for next-generation display and optoelectronic technologies. Currently, it is challenging to obtain CPL materials with both large luminescence dissymmetry factor (glum) and high quantum yield (Φ). A pair of enantiomeric N N C-type Pt(II) complexes (L/D)-1 modified with chiral Leucine methyl ester are presented herein. Though the solutions of these complexes are CPL-inactive, the spin-coated thin films of (L/D)-1 exhibit giantly-amplified circularly polarized phosphorescences with |glum| of 0.53 at 560 nm and Φair of ~50 %, as well as appealing circular dichroism (CD) signals with the maximum absorption dissymmetry factor |gabs| of 0.37-0.43 at 480 nm. This superior CPL performance benefits from the hierarchical formation of crystalline fibrillar networks upon spin coating. Comparative studies of another pair of chiral Pt(II) complexes (L/D)-2 with a symmetric N C N coordination mode suggest that the asymmetric N N C coordination of (L/D)-1 are favorable for the efficient exciton delocalization to amplify the CPL performance. Optical applications of the thin films of (L/D)-1 in CPL-contrast imaging and inducing CP light generation from achiral emitters and common light-emitting diode lamps have been successfully realized.

Dual Enhancement of Phosphorescence and Circularly Polarized Luminescence through Entropically Driven Self-Assembly of a Platinum(II) Complex.

Addressing the dual enhancement of circular polarization (glum) and luminescence quantum yield (QY) in circularly polarized luminescence (CPL) systems poses a significant challenge. In this study, we present an innovative strategy utilizing the entropically driven self-assembly of amphiphilic phosphorescent platinum(II) complexes (L-Pt) with tetraethylene glycol chains, resulting in unique temperature dependencies. The entropically driven self-assembly of L-Pt leads to a synergistic improvement in phosphorescence emission efficiency (QY was amplified from 15 % at 25 °C to 53 % at 60 °C) and chirality, both in the ground state and the excited state (glum value has been magnified from 0.04×10-2 to 0.06) with increasing temperature. Notably, we observed reversible modulation of phosphorescence and chirality observed over at least 10 cycles through successive heating and cooling, highlighting the intelligent control of luminescence and chiroptical properties by regulating intermolecular interactions among neighboring L-Pt molecules. Importantly, the QY and glum of the L-Pt assembly in solid state were measured as 69 % and 0.16 respectively, representing relatively high values compared to most self-assembled CPL systems. This study marks the pioneering demonstration of dual thermo-enhancement of phosphorescence and CPL and provides valuable insights into the thermal effects on high-temperature and switchable CPL materials.

Regioselective C(sp2)-C(sp3) Coupling Mediated by Classical and Rollover Cyclometalation.

By taking advantage of a sequence of oxidative addition/reductive elimination reactions, Pt(II) cyclometalated derivatives are able to promote a rare C(sp2)-C(sp3) bond coupling, resulting in the production of novel methyl-substituted pyridines and bipyridines. Starting from 6-phenyl-2,2'-bipyridine, the step-by-step full sequence of reactions has been followed, leading to the unprecedented 3-methyl-6-phenyl-2,2'-bipyridine, which was isolated and fully characterized. The synthesis involves the following steps: (1) rollover cyclometalation to give the starting complex [Pt(N^C)(DMSO)Me]; (2) the synthesis of a more electron-rich complex [Pt(N^C)(PPh3)Me] by the substitution of DMSO with triphenylphosphine; (3) oxidative addition with methyl iodide to give the Pt(IV) complex [Pt(N^C)(PPh3)(Me)2(I)]; (4) iodide abstraction with silver tetrafluoborate to give an unstable pentacoordinate intermediate, which rapidly evolves through a carbon-carbon reductive coupling, forming a new C(sp3)-C(sp2) bond; (5) finally, the extrusion and characterization of the newly formed 3-methyl-6-phenyl-2,2'-bipyridine. The reaction has been therefore extended to a well-known classical cyclometalating ligand, 2-phenylpyridine, demonstrating that the method is not restricted to rollover derivatives. Following the same step-by-step procedure, 2-phenylpyridine was converted to 2-o-tolyl-pyridine, displaying the potential application of the method to the larger family of classical cyclometalated complexes. The application of this protocol may be useful to convert an array of heterocyclic compounds to their methyl- or alkyl-substituted analogs.

Palladium and platinum complexes based on pyridine bases induced anticancer effectiveness via apoptosis protein signaling in cancer cells.

Palladium and platinum complexes, especially those that include cisplatin, can be useful chemotherapeutic drugs. Alternatives that have less adverse effects and require lower dosages of treatment could be provided by complexes containing pyridine bases. The complexes [Pd(SCN)2(4-Acpy)2] (1), [Pd(N3)2(4-Acpy)2] (2) [Pd(paOH)2].2Cl (3) and [Pt(SCN)2(paO)2] (4) were prepared by self-assembly method at ambient temperature; (4-Acpy = 4-acetylpyridine and paOH = pyridine-2-carbaldehyde-oxime). The structure of complexes 1-4 was confirmed using spectroscopic and X-ray crystallography methods. Complexes 1-4 have similar features in isomerism that include the trans coordination geometry of pyridine ligands with Pd or Pt ion. The 3D network structure of complexes 1-4 was constructed by an infinite number of discrete mononuclear molecules extending via H-bonds. The Pd and Pt complexes 1-4 with pyridine ligands were assessed on MCF-7, T47D breast cancer cells and HCT116 colon cancer cells. The study evaluated cell death through apoptosis and cell cycle phases in MCF-7 cells treated with palladium or platinum conjugated with pyridine base. Upon treatment of MCF-7 with these complexes, the expression of apoptotic signals (Bcl2, p53, Bax and c-Myc) and cell cycle signals (p16, CDK1A, CDK1B) were evaluated. Compared to other complexes and cisplatin, IC50 of complex 1 was lowest in MCF-7 cells and complex 2 in T47D cells. Complex 4 has the highest effectiveness on HCT116. The selective index (SI) of complexes 1-4 has a value of more than two for all cancer cell lines, indicating that the complexes were less toxic to normal cells when given the same dose. MCF-7 cells treated with complex 2 and platinum complex 4 exhibited the highest level of early apoptosis. p16 may be signal arrest cells in Sub G, which was observed in cells treated with palladium complexes that suppress excessive cell proliferation. High c-Myc expression of treated cells with four complexes 1-4 and cisplatin could induce p53. All complexes 1-4 elevated the expression of Bax and triggered by the tumor suppressor gene p53. p53 was downregulating the expression of Bcl2.

Bioconjugate based on cisplatin and bacterial exopolysaccharide with reduced side effects: A novel proposal for cancer treatment.

BACKGROUND: In the search for alternatives that attenuate the toxicity associated to oncologic treatment with cisplatin (CDDP) and considering the potential health-beneficial properties of exopolysaccharides (EPS) produced by lactic acid bacteria, it was aimed on this study to evaluate the cytotoxic, toxicologic and antitumoral efficacy of a bioconjugate based on CDDP and EPS, on the experimental tumor of sarcoma 180. METHODS: After the synthesis of the cis-[Pt(NH3)2(Cl)2] complex and of the conjugate containing Lactobacillus fermentum exopolysaccharide was tested both in vitro and in vivo for evaluating the acute toxicity. RESULTS: The antitumoral study was performed using mice transplanted with sarcoma 180. The bioconjugate showed low to medium cytotoxicity for the cell lines tested, as well moderated acute toxicity. After determining the LD50, the following experimental groups were established for the antitumor assay: Control (NaCl 0,9%), CDDP (1 mg/kg), EPS and bioconjugate composition (200 mg/kg). The bioconjugate promoted a 38% regression in tumor mass when compared to the control, and a regression of 41% when compared to CDDP. Liver histopathological analysis revealed discrete alterations in animals treated with (CDDP + EPS) when compared to control. The bioconjugate also minimized changes in the renal parenchyma resulting from the tumor. CONCLUSION: Our results indicate that when CDDP is associated with EPS, this composition was more biocompatible, showing itself as a potent chemotherapeutic agent and lower tissue toxicity.

Synthesis and Characterisation of Platinum(II) Diaminocyclohexane Complexes with Pyridine Derivatives as Anticancer Agents.

Cisplatin-type covalent chemotherapeutics are a cornerstone of modern medicinal oncology. However, these drugs remain encumbered with dose-limiting side effects and are susceptible to innate and acquired resistance. The bulk of platinum anticancer research has focused on Cisplatin and its derivatives. Here, we take inspiration from the design of platinum complexes and ligands used successfully with other metals to create six novel complexes. Herein, the synthesis, characterization, DNA binding affinities, and lipophilicity of a series of non-traditional organometallic Pt(II)-complexes are described. These complexes have a basic [Pt(PL)(AL)]Cl2 molecular formula which incorporates either 2-pyrrolidin-2-ylpyridine, 2-(1H-Imidazol-2-yl)pyridine, or 2-(2-pyridyl)benzimidazole as the PL; the AL is resolved diaminocyclohexane. Precursor [Pt(PL)(Cl)2] complexes were also characterized for comparison. While the cytotoxicity and DNA binding properties of the three precursors were unexceptional, the corresponding [Pt(PL)(AL)]2+ complexes were promising; they exhibited different DNA binding interactions compared with Cisplatin but with similar, if not slightly better, cytotoxicity results. Complexes with 2-pyrrolidin-2-ylpyridine or 2-(2-pyridyl)benzimidazole ligands had similar DNA binding properties to those with 2-(1H-Imidazol-2-yl)pyridine ligands but were not as cytotoxic to all cell lines. The variation in activity between cell lines was remarkable and resulted in significant selectivity indices in MCF10A and MCF-7 breast cancer cell lines, compared with previously described similar Pt(II) complexes such as 56MESS.

Vapor-Induced Assembly of a Platinum(II) Complex Loaded on Layered Double Hydroxide Nanoparticles.

Controlled self-assembly of PtII complexes is key to the development of optical and stimuli-responsive materials, but designing and precisely controlling them is still difficult owing to weak intermolecular interactions. Herein, we report the successful water-vapor-induced assembly of an anionic PtII complex [Pt(CN)2 (ppy)]- (Hppy=2-phenylpyridine) electrostatically loaded onto cationically charged layered double hydroxide (LDH) nanoparticles consisting of Mg2+ and Al3+ ions. When the PtII complexes were densely loaded onto the LDH nanoparticles, the assembly was maintained, even in dilute aqueous media. In the case of sparse loading, the PtII complexes were loaded discretely in the dry state; however, when water vapor was adsorbed, the increased mobility of the PtII complexes led to their assembly on the LDH nanoparticles. The presence of water vapor led to a drastic change in luminescence from green to orange.

From Basics of Coordination Chemistry to Understanding Cisplatin-analogue Pt Drugs.

BACKGROUND: Cisplatin, a platinum complex discovered by Rosenberg in 1969, has long been known as the first metal-based anticancer agent. Since then, various similar derivatives of cisplatin have been investigated for pharmacological activity, and the approved complexes have been applied as drugs. OBJECTIVES: The aims of the current study are: 1) to summarize the advantages and dose-limiting effects of the approved and unapproved chemotherapy platinum cytostatics, 2) to develop new strategies for the development of platinum anticancer drugs, and 3) to clarify the important factors for the mechanism of action of platinum complexes. METHODS: A search was conducted in the literature databases, and the obtained information was summarized and analyzed. RESULTS: Myelosuppression is the main dose-limiting effect and the reason for the disapproval of platinum complexes, such as picoplatin, enloplatin, miboplatin, sebriplatin, zeniplatin, spiroplatin, iproplatin, and ormaplatin. From the basic point of view of inorganic coordination chemistry, such as theoretical calculations, crystal structures of model complexes, docking structures with nucleic acid molecules, spectroscopy, and biological aspects, the importance of physicochemical properties of inorganic platinum complexes for their mechanism of action has been indicated. Spectroscopic methods, such as FTIR, NMR, X-ray crystal structure analysis, and fluorescence microscopy, are important for the investigation of the conformational changes in the binding of platinum complexes and DNA. CONCLUSION: In the development of platinum complexes, strong anti-cancer drug activity, low toxicity, and resistance can be obtained by the application of polynuclear platinum agents, complexes with targeted activity, and nanoparticle formulations. Electronic structure, stereochemical, and thermodynamic properties are essential for understanding the reaction mechanism of platinum complexes.

The Role of Inverted Ligand Field in the Electronic Structure and Reactivity of Octahedral Formal Platinum (IV) Complexes.

Platinum complexes are ubiquitous in chemistry and largely used as catalysts or as precursors in drug chemistry, thus a deep knowledge of their electronic properties may help in planning new synthetic strategies or exploring new potential applications. Herein, the electronic structure of many octahedral platinum complexes is drastically revised especially when they feature electronegative elements such as halogens and chalcogens. The investigation revealed that in most cases the five d platinum orbitals are invariably full, thus the empty antibonding orbitals, usually localized on the metal, are mainly centered on the ligands, suggesting a questionable assignment of formal oxidation state IV. The analysis supports the occurrence of the inverted ligand field theory in all cases with the only exceptions of the Pt-F and Pt-O bonding. The trends for the molecular complexes are mirrored also by the density of states plots of extended structures featuring octahedral platinum moieties in association with chalcogens atoms. Finally, the oxidative addition of a Se-Cl linkage to a square platinum complex to achieve an octahedral moiety has been revised in the framework of the inverted ligand field.

Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells.

The purine derivative fludarabine is part of frontline therapy for chronic lymphocytic leukaemia (CLL). It has shown positive effects on solid tumours such as melanoma, breast, and colon carcinoma in clinical phase I studies. As the treatment of CLL cells with combinations of fludarabine and metal complexes of antitumoural natural products, e.g., illudin M ferrocene, has led to synergistically enhanced apoptosis, in this research study different complexes of fludarabine itself. Four complexes bearing a trans-[Br(PPh3)2]Pt/Pd fragment attached to atom C-8 via formal η1-sigma or η2-carbene bonds were synthesised in two or three steps without protecting polar groups on the arabinose or adenine. The platinum complexes were more cytotoxic than their palladium analogues, with low single-digit micromolar IC50 values against cells of various solid tumour entities, including cisplatin-resistant ones and certain B-cell lymphoma and CLL, presumably due to the ten-fold higher cellular uptake of the platinum complexes. However, the palladium complexes interacted more readily with isolated Calf thymus DNA. Interestingly, the platinum complexes showed vastly greater selectivity for cancer over non-malignant cells when compared with fludarabine.

Synthesis and structure of two novel trans-platinum complexes.

Here for the first time the synthesis and characterization of two new trans-platinum complexes, trans-[PtCl2{HN=C(OH)C6H5}2] (compound 1) and trans-[PtCl4(NH3){HN=C(OH)tBu}] (compound 2) [with tBu = C(CH3)3] are described. The structures have been characterized using nuclear magnetic resonance spectroscopy and X-ray single-crystal diffraction. In compound 1 the platinum cation, at the inversion center, is in the expected square-planar coordination geometry. It is coordinated to two chloride anions, trans to each other, and two nitrogen atoms from the benzamide ligands. The van der Waals interactions between the molecules produce extended two-dimensional layers that are linked into a three-dimensional structure through π...π intermolecular interactions. In compound 2 the platinum cation is octahedrally coordinated by four chloride anions and two nitrogen atoms from the pivalamide and ammine ligands, in trans configuration. The molecular packing is governed by intermolecular hydrogen bonds and van der Waals interactions.

Triphenylphosphonium-functionalized N-heterocyclic carbene platinum complexes [(NHC-TPP+)Pt] induce cell death of human glioblastoma cancer stem cells.

A growing body of experimental and clinical evidence suggests that rare cell populations, known as cancer stem cells (CSCs), play an important role in the development and therapeutic resistance of several cancers, including glioblastoma. Elimination of these cells is therefore of paramount importance. Interestingly, recent results have shown that the use of drugs that specifically disrupt mitochondria or induce mitochondria-dependent apoptosis can efficiently kill cancer stem cells. In this context, a novel series of platinum(II) complexes bearing N-heterocyclic carbene (NHC) of the type [(NHC)PtI2(L)] modified with the mitochondria targeting group triphenylphosphonium were synthesized. After a complete characterization of the platinum complexes, the cytotoxicity against two different cancer cell lines, including a cancer stem cell line, was investigated. The best compound reduced the cell viability of both cell lines by 50% in the low µM range, with an approximately 300-fold higher anticancer activity on the CSC line compared to oxaliplatin. Finally, mechanistic studies showed that the triphenylphosphonium functionalized platinum complexes significantly altered mitochondrial function and also induced atypical cell death.

Antitumor Activity and Reductive Stress by Platinum(II) N-Heterocyclic Carbenes based on Guanosine.

Platinum(II) complexes bearing N-heterocyclic carbenes based guanosine and caffeine have been synthesized by unassisted C-H oxidative addition, leading to the corresponding trans-hydride complexes. Platinum guanosine derivatives bearing triflate as counterion or bromide instead of hydride as co-ligand were also synthesized to facilitate correlation between structure and activity. The hydride compounds show high antiproliferative activity against all cell lines (TC-71, MV-4-11, U-937 and A-172). Methyl Guanosine complex 3, bearing a hydride ligand, is up to 30 times more active than compound 4, with a bromide in the same position. Changing the counterion has no significant effect in antiproliferative activity. Increasing bulkiness at N7, with an isopropyl group (compound 6), allows to maintain the antiproliferative activity while decreasing toxicity for non-cancer cells. Compound 6 leads to an increase in endoplasmic reticulum and autophagy markers on TC71 and MV-4-11 cancer cells, induces reductive stress and increases glutathione levels in cancer cells but not in non-cancer cell line HEK-293.

Enhancing Pt(IV) Complexes' Anticancer Activity upon Encapsulation in Stimuli-Responsive Nanocages.

Platinum-based chemotherapy is the first-line treatment for different cancer types, and in particular, for malignant pleural mesothelioma patients (a tumor histotype with urgent medical needs). Herein, a strategy is presented to stabilize, transport, and intracellularly release a platinumIV (PtIV ) prodrug using a breakable nanocarrier. Its reduction, and therefore activation as an anticancer drug, is promoted by the presence of glutathione in neoplastic cells that also causes the destruction of the carrier. The nanocage presents a single internal cavity in which the hydrophobic complex (Pt(dach)Cl2 (OH)2 ), (dach = R,R-diaminocyclohexane) is encapsulated. The in vitro uptake and the internalization kinetics in cancer model cells are evaluated and, using flow cytometry analysis, the successful release and activation of the Pt-based drug inside cancer cells are demonstrated. The in vitro findings are confirmed by the in vivo experiments on a mice model obtained by xenografting MPM487, a patient-derived malignant pleural mesothelioma. MPM487 confirms the well-known resistance of malignant pleural mesothelioma to cisplatin treatment while an interesting 50% reduction of tumor growth is observed when mice are treated with the PtIV , entrapped in the nanocages, at an equivalent dose of the platinum complex.

DNA binding properties and cytotoxic effects of two double rollover cycloplatinated (II) complexes on cancer cell lines.

In this study, the DNA binding capacity and cytotoxic effects of two double rollovers cycloplatinated complexes, [Pt2(µ-bpy-2H)(CF3COO)2(PPh3)2] and [Pt2(µ-bpy-2H)(I)2(PPh3)2] denoted as C1 and C2, respectively, were evaluated. By using UV-Visible spectroscopy the intrinsic binding constant (Kb) of C1 and C2 to DNA were determined as 2.9 × 105 M-1, and 5.4 × 105 M-1, respectively. Both the compounds were able to quench the fluorescence of ethidium bromide as a well known DNA intercalator. The calculated Stern-Volmer quenching constants (Ksv) for C1 and C2 were 3.5 × 103 M-1, and 1.2 × 104 M-1, respectively. Upon interaction of both the compounds with DNA, increase in viscosity of DNA solution were observed, further confiming the involvement of intercalative interactions between the complexes and DNA. The cytotoxic effects of complexes in compare to cisplatin were evaluated on different cancer cell lines by MTT assay. Interestingly, C2 showed the highest cytotoxicity on A2780R, a cisplatin resistant-cell line. Induction of apoptosis by the complexes was proved by flowcytometry. In all the studied cell lines, the extent of apoptosis induced by C2 was comparable or higher than cisplatin. Cisplatin induced more necrosis in all the cancer cell lines in the tested concentration.

A Non-Conventional Platinum Drug against a Non-Small Cell Lung Cancer Line.

A dinuclear Pt(II) complex with putrescine as bridging polyamine ligand ([Pt2Put2(NH3)4]Cl4) was synthesized and assessed as to its potential anticancer activity against a human non-small cell lung cancer line (A549), as well as towards non-cancer cells (BEAS-2B). This effect was evaluated through in vitro cytotoxicity assays (MTT and SRB) coupled to microFTIR and microRaman spectroscopies, the former delivering information on growth-inhibiting and cytotoxic abilities while the latter provided very specific information on the metabolic impact of the metal agent (at the sub-cellular level). Regarding cancer cells, a major impact of [Pt2Put2(NH3)4]Cl4 was evidenced on cellular proteins and lipids, as compared to DNA, particularly via the Amide I and Amide II signals. The effect of the chelate on non-malignant cells was lower than on malignant ones, evidencing a promising low toxicity towards healthy cells.

PtOx Cly (OH)z (H2 O)n Complexes under Oxidative and Reductive Conditions: Impact of the Level of Theory on Thermodynamic Stabilities.

Platinum-based catalysts with Cl- , OH- , O2- and H2 O ligands, are involved in many industrial processes. Their final chemical properties are impacted by calcination and reduction applied during the preparation and activation steps. We investigate their stability under these reactive conditions with density functional theory (DFT). We benchmark various functionals (PBE-dDsC, optPBE, B3LYP, HSE06, PBE0, TPSS, RTPSS and SCAN) against ACFDT-RPA. PBE-dDsC is well adapted, although hybrid functionals are more accurate for redox reactions. Thermodynamic phase diagrams are determined by computing the chemical potential of the species as a function of temperature and partial pressures of H2 O, HCl, O2 and H2 . The stability and nature of the Pt species are highly sensitive to the activation conditions. Under O2 , high temperatures favour PtO2 while under H2 , platinum is easily reduced to Pt(0). Chlorine modifies the coordination sphere of platinum during calcination by stabilizing PtCl4 and shifts the reduction of platinum to higher temperatures under H2 .

Organometallic Platinum(II) Photosensitisers that Demonstrate Ligand-Modulated Triplet-Triplet Annihilation Energy Upconversion Efficiencies.

A series of 2-phenylquinoxaline ligands have been synthesised that introduce either CF3 or OCF3 electron-withdrawing groups at different positions of the phenyl ring. These ligands were investigated as cyclometalating reagents for platinum(II) to give neutral complexes of the form [Pt(C^N)(acac)] (in which C^N=cyclometalating ligand; acac=acetyl acetonate). X-ray crystallographic studies on three examples showed that the complexes adopt an approximate square planar geometry. All examples revealed strong Pt-Pt linear contacts of 3.2041(6), 3.2199(3) and 3.2586(2) Å. The highly coloured complexes display efficient visible absorption at 400-500 nm (ϵ ≈5000 M-1  cm-1 ) and orange red photoluminescent characteristics (λem =603-620 nm; Φem ≤37 %), which were subtly tuned by the ligand. Triplet emitting character was confirmed by microsecond luminescence lifetimes and the photogeneration of singlet oxygen with quantum efficiencies up to 57 %. Each complex was investigated as a photosensitiser for triplet-triplet annihilation energy upconversion using 9,10-diphenylanthracene as the annihilator species: a range of good upconversion efficiencies (ΦUC 5.9-14.1 %) were observed and shown to be strongly influenced by the ligand structure in each case.

Trans-[bis(benzimidazol-2-ylidene)dichlorido]platinum(II) complexes with peculiar modes of action and activity against cisplatin-resistant cancer cells.

Three series of cis- and trans-[bis(benzimidazol-2-ylidene)dichlorido]platinum(II) and cis-[(benzimidazol-2-ylidene)(DMSO)dichlorido]platinum(II) complexes were synthesised and screened for cytotoxicity against six human cancer cell lines. Depending on their N-alkyl and 5-alkoxycarbonyl substituents, two-digit nanomolar to single-digit micromolar IC50 values against cancer cell lines intrinsically resistant to or ill-responding to cisplatin were reached by both cis- and trans-configured complexes. The stability of the complexes under aqueous biotest conditions was shown via 1H and 195Pt NMR monitoring to be dependent on their configuration and their N-substituents. Localisation studies employing click reactions with 1-alkyne- or cyclopropene-tagged derivatives revealed that the cis-complexes accumulated in the cell nuclei and the trans-complexes in the mitochondria. While the most active cis-complexes showed modes of action akin to those of cisplatin, the most active trans-complexes differed from cisplatin by much lower rates of cellular uptake and ROS production, and by their non-interaction with the cell cycle and the DNA of cancer cells. Thus, we identified structural key elements for the synthesis of optimised trans-configured NHC platinum(II) complexes with high activity also against cisplatin-refractory cancer cells.