Diastereoselective Synthesis of Sulfoxide-Functionalised N-Heterocyclic Carbene Ruthenium Complexes, Experimental and Computational Study.

The synthesis of sulfoxide-functionalized NHC ligand precursors were carried out by direct and mild oxidation from corresponding thioether precursors with high selectivity. A series of cationic [Ru(II)(η6-p-cymene)(NHC-SO)Cl]+ complexes were obtained in excellent yields by the classical Ag2O transmetallation route. NMR analyses suggested a chelate structure for the metal complexes, and X-ray diffractometry studies of 4 complexes unambiguously confirmed the preference for the bidentate (κ2-C,S) coordination mode of the NHC-SO ligands. Interestingly, only one diastereomer, in the form of an enantiomeric pair, was observed both in 1H NMR and in the solid state for the complexes. DFT calculations showed a possible intrinsic energy difference between the two pairs of diastereomers. The calculated energy barriers suggested that inversion of the sulfoxide is only plausible from the higher energy diastereomer together with bulky substituents. Inverting the configuration at the Ru center instead shows a lower and accessible activation barrier to provide the most stable diastereomer through thermodynamic control, consistent with the observation of a single species by 1H NMR as a pair of enantiomers. All these complexes catalyse the ß-alkylation of secondary alcohols.

A stable and true-blue emissive hexacoordinate Si(IV) N-heterocyclic carbene complex and its use in organic light-emitting diodes.

A neutral hexacoordinate Si(IV) complex containing two tridentate N-heterocyclic carbene ligands is synthesised and characterized by X-ray crystallography, optical spectroscopy, electrochemistry and computational methods. The stable compound exhibits remarkable deep-blue photoluminescence particularly in the solid state, which enables its use as an electroluminescent material in organic light-emitting diodes.

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.

Rh(I) Complexes with Hemilabile Thioether-Functionalized NHC Ligands as Catalysts for [2 + 2 + 2] Cycloaddition of 1,5-Bisallenes and Alkynes.

The [2 + 2 + 2] cycloaddition of 1,5-bisallenes and alkynes under the catalysis of Rh(I) with hemilabile thioether-functionalized N-heterocyclic carbene ligands is described. This protocol effectively provides an entry to different trans-5,6-fused bicyclic systems with two exocyclic double bonds in the cyclohexene ring. The process is totally chemoselective with the two internal double bonds of the 1,5-bisallenes being involved in the cycloaddition. The complete mechanism of this transformation as well as the preference for the trans-fusion over the cis-fusion has been rationalized by density functional theory calculations. The reaction follows a typical [2 + 2 + 2] cycloaddition mechanism. The oxidative addition takes place between the alkyne and one of the allenes and it is when the second allene is inserted into the rhodacyclopentene that the trans-fusion is generated. Remarkably, the hemilabile character of the sulfur atom in the N-heterocyclic carbene ligand modulates the electron density in key intermediates, facilitating the overall transformation.

Polyethylenimine, an Autophagy-Inducing Platinum-Carbene-Based Drug Carrier with Potent Toxicity towards Glioblastoma Cancer Stem Cells.

The difficulty involved in the treatment of many tumours due to their recurrence and resistance to chemotherapy is tightly linked to the presence of cancer stem cells (CSCs). This CSC sub-population is distinct from the majority of cancer cells of the tumour bulk. Indeed, CSCs have increased mitochondrial mass that has been linked to increased sensitivity to mitochondrial targeting compounds. Thus, a platinum-based polyethylenimine (PEI) polymer-drug conjugate (PDC) was assessed as a potential anti-CSC therapeutic since it has previously displayed mitochondrial accumulation. Our results show that CSCs have increased specific sensitivity to the PEI carrier and to the PDC. The mechanism of cell death seems to be necrotic in nature, with an absence of apoptotic markers. Cell death is accompanied by the induction of a protective autophagy. The interference in the balance of this pathway, which is highly important for CSCs, may be responsible for a partial reversion of the stem-like phenotype observed with prolonged PEI and PDC treatment. Several markers also indicate the cell death mode to be capable of inducing an anti-cancer immune response. This study thus indicates the potential therapeutic perspectives of polycations against CSCs.

Observation of Hyperpositive Non-Linear Effect in Asymmetric Organozinc Alkylation in Presence of N-Pyrrolidinyl Norephedrine.

Phenomena related to asymmetric amplification are considered to be key to understanding the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been studied to understand such chiral amplification, in particular based on non-linear effects. Three decades after the theoretical demonstration that a chiral catalyst, when not enantiopure, could be more enantioselective than its enantiopure counterpart, we show here a new experimental example of nonlinear hyperpositive effect. We report here our investigations in the enantioselective zinc-catalyzed alkylation of benzaldehyde with N-pyrrolidinyl norephedrine as partially resolved chiral ligand, which shows a significant hyperpositive non-linear effect. A study of the underlying mechanism was conducted, which allows us to confirm a mechanism that implies a monomeric and a dimeric complex both catalyzing the reaction at a steady state and giving different enantioselectivities.

Evaluation of the Cytotoxicity of Cationic Polymers on Glioblastoma Cancer Stem Cells.

Cationic polymers such as polyethylenimine (PEI) have found a pervasive place in laboratories across the world as gene delivery agents. However, their applications are not limited to this role, having found a place as delivery agents for drugs, in complexes known as polymer-drug conjugates (PDCs). Yet a potentially underexplored domain of research is in their inherent potential as anti-cancer therapeutic agents, which has been indicated by several studies. Even more interesting is the recent observation that certain polycations may present a significantly greater toxicity towards the clinically important cancer stem cell (CSC) niche than towards more differentiated bulk tumour cells. These cells, which possess the stem-like characteristics of self-renewal and differentiation, are highly implicated in cancer drug resistance, tumour recurrence and poor clinical prognosis. The search for compounds which may target and eliminate these cells is thus of great research interest. As such, the observation in our previous study on a PEI-based PDC which showed a considerably higher toxicity of PEI towards glioblastoma CSCs (GSCs) than on more differentiated glioma (U87) cells led us to investigate other cationic polymers for a similar effect. The evaluation of the toxicity of a range of different types of polycations, and an investigation into the potential source of GSC's sensitivity to such compounds is thus described.

Polymerization/depolymerization of chiral metallo-supramolecular assembly induced by redox change.

We report on the polymerization/depolymerization of chiral metallo-supramolecular assembly by CuI /CuII redox change. By combining a monotopic enantiopure ligand with a ditopic ligand of opposite configuration, ML2 -type complexes are generated with chiral self-recognition or self-discrimination depending on the oxidation state of copper. In presence of CuI , the formation of heterochiral complexes is favored, thus generating dinuclear species whereas CuII advocates for the formation of homochiral species, namely, a mixture of mononuclear species and metallo-supramolecular polymeric species. Thus, cyclic voltammetry was used to study such a chirality-induced stimulus sensitive polymerization/depolymerization process.

In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma.

We describe here the evaluation of the cytotoxic efficacy of two platinum (II) complexes bearing an N-heterocyclic carbene (NHC) ligand, a pyridine ligand and bromide or iodide ligands on a panel of human metastatic cutaneous melanoma cell lines representing different genetic subsets including BRAF-inhibitor-resistant cell lines, namely A375, SK-MEL-28, MeWo, HMCB, A375-R, SK-MEL-5-R and 501MEL-R. Cisplatin and dacarbazine were also studied for comparison purposes. Remarkably, the iodine-labelled Pt-NHC complex strongly inhibited proliferation of all tested melanoma cells after 1-h exposure, likely due to its rapid uptake by melanoma cells. The mechanism of this inhibitory activity involves the formation of DNA double-strand breaks and apoptosis. Considering the intrinsic chemoresistance of metastatic melanoma cells of current systemic treatments, these findings are promising and could give research opportunities in the future to improve the prognosis of patients suffering from unresectable metastatic melanoma that are not eligible or that do not respond to the most effective drugs available to date, namely BRAF inhibitors and the anti-PD-1 monoclonal antibody (mAb).

Observation of hyperpositive non-linear effect in catalytic asymmetric organozinc additions to aldehydes.

Asymmetric amplification is a phenomenon that is believed to play a key role in the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been investigated to provide an understanding of how chiral amplification is possible, in particular based on non-linear effects. Interestingly, it has been proposed a quarter century ago that chiral catalysts, when not enantiopure might even be more enantioselective than their enantiopure counterparts. We show here that such hyperpositive non-linear effect in asymmetric catalysis is indeed possible. An in-depth study into the underlying mechanism was carried out, and the scheme we derive differs from the previous proposed models.

N-Heterocyclic Carbene Platinum(IV) as Metallodrug Candidates: Synthesis and 195Pt NMR Chemical Shift Trend.

A series of octahedral platinum(IV) complexes functionalized with both N-heterocyclic carbene (NHC) ligands were synthesized according to a straightforward procedure and characterized. The coordination sphere around the metal was varied, investigating the influence of the substituted NHC and the amine ligand in trans position to the NHC. The influence of those structural variations on the chemical shift of the platinum center were evaluated by 195Pt NMR. This spectroscopy provided more insights on the impact of the structural changes on the electronic density at the platinum center. Investigation of the in vitro cytotoxicities of representative complexes were carried on three cancer cell lines and showed IC50 values down to the low micromolar range that compare favorably with the benchmark cisplatin or their platinum(II) counterparts bearing NHC ligands.

Chiral stimuli-responsive metallo-supramolecular assembly induced by CuII/CuI redox change.

We investigated the selective formation of homoleptic and heteroleptic metal complexes controlled by means of the chiral molecular instruction of the ligand and the coordination geometry of the metal. Our results showed that chiral self-recognition or self-discrimination may be induced by the CuI/CuII redox transition using cyclic voltammetry. The further use of chiral ditopic ligands led to metallo-supramolecular copolymers with stimuli-responsive controlled arrangement.

Phosphorescent Cationic Heterodinuclear IrIII /MI Complexes (M=CuI , AuI ) with a Hybrid Janus-Type N-Heterocyclic Carbene Bridge.

A novel class of phosphorescent cationic heterobimetallic IrIII /MI complexes, where MI =CuI (4) and AuI (5), is reported. The two metal centers are connected by the hybrid bridging 1,3-dimesityl-5-acetylimidazol-2-ylidene-4-olate (IMesAcac) ligand that combines both a chelating acetylacetonato-like and a monodentate N-heterocyclic carbene site coordinated onto an IrIII and a MI center, respectively. Complexes 4 and 5 have been prepared straightforwardly by a stepwise site-selective metalation with the zwitterionic [(IPr)MI (IMesAcac)] metalloproligand (IPr=1,3-(2,6-diisopropylphenyl)-2H-imidazol-2-ylidene) and they have been fully characterized by spectroscopic, electrochemical, and computational investigation. Complexes 4 and 5 display intense red emission arising from a low-energy excited state that is located onto the "Ir(C^N)" moiety featuring an admixed triplet ligand-centered/metal-to-ligand charge transfer (3 IL/1 MLCT) character. Comparison with the benchmark mononuclear complexes reveals negligible electronic coupling between the two distal metal centers at the electronic ground state. The bimetallic systems display enhanced photophysical properties in comparison with the parental congeners. Noteworthy, similar non-radiative rate constants have been determined along with a two-fold increase of radiative rate, yielding brightly red-emitting cyclometalating IrIII complexes. This finding is ascribed to the increased MLCT character of the emitting state in complexes 4 and 5 due to the smaller energy gap between the 3 IL and 1 MLCT manifolds, which mix via spin-orbit coupling.

Synthesis, characterization, catalytic and biological application of half-sandwich ruthenium complexes bearing hemilabile (κ2-C,S)-thioether-functionalised NHC ligands.

A series of cationic Ru(ii)(η6-p-cymene) complexes with thioether-functionalised N-heterocyclic carbene ligands have been prepared and fully characterized. Steric and electronic influence of the R thioether substituent on the coordination of the sulfur atom was investigated. The molecular structure of three of them has been determined by means of X-ray diffractrometry and confirmed the bidentate (κ2-C,S) coordination mode of the ligand. Interestingly, only a single diastereomer, as an enantiomeric couple, was observed in the solid state for complexes 1c, 1i and 1j. DFT calculations established a low energy inversion barrier between the two diastereomers through a sulfur pyramidal inversion pathway with R donating group while a dissociative/associative mechanism is more likely with R substituents that contain electron withdrawing group, thus suggesting that the only species observed by the 1H-NMR correspond to an average resonance position of a fluxional mixtures of isomers. All these complexes were found to catalyse the oxydant-free double dehydrogenation of primary amine into nitrile. Ru complex bearing NHC-functionalised S-tBu group was further investigated in a wide range of amines and was found more selective for alkyl amine substrates than for benzylamine derivatives. Finally, preliminary results of the biological effects on various human cancer cells of four selected Ru complexes are reported.

Hyperpositive non-linear effects: enantiodivergence and modelling.

The chiral ligand N-methylephedrine (NME) was found to catalyse the addition of dimethylzinc to benzaldehyde in an enantiodivergent way, with a monomeric and a homochiral dimeric complex both catalysing the reaction at a steady state and giving opposite product enantiomers. A change in the sign of the enantiomeric product was thus possible by simply varying the catalyst loading or the ligand ee, giving rise to an enantiodivergent non-linear effect. Simulations using a mathematical model confirmed the possibility of such behaviour and showed that this can lead to situations where a reaction gives racemic products, although the system is composed only of highly enantioselective individual catalysts. Furthermore, depending on the dimer's degree of participation in the catalytic conversion, enantiodivergence may or may not be observed experimentally, which raises questions about the possibility of enantiodivergence in other monomer/dimer-catalysed systems. Simulations of the reaction kinetics showed that the observed kinetic constant k obs is highly dependent on user-controlled parameters, such as the catalyst concentration and the ligand ee, and may thus vary in a distinct way from one experimental setup to another. This unusual dependency of k obs allowed us to confirm that a previously observed U-shaped catalyst order vs. catalyst loading-plot is linked to the simultaneous catalytic activity of both monomeric and dimeric complexes.

Chiral Self-Sorting Process with Ditopic Ligands: Alternate or Block Metallopolymer Assembly as a Function of the Metal Ion.

We report an extensive study on the coordination behavior of chiral ditopic bridging ligands, which lead to metallosupramolecular polymers in the presence of Zn(II) and Cu(II) in solution. With the help of UV-vis and circular dichroism spectroscopies, we show that the metallopolymer sequence can be controlled by chirality and by the choice of the metal ion. Although the formation of a block metallopolymer proceeds through the assembly of homoleptic complexes, an alternate metallopolymer may be obtained only when heteroleptic complexes are formed. This demonstrates how the prevalent coordination geometries at metal centers may be used to control the sequences of the metallopolymers.

Structural and Luminescent Properties of Homoleptic Silver(I), Gold(I), and Palladium(II) Complexes with nNHC-tzNHC Heteroditopic Carbene Ligands.

Novel silver(I), gold(I), and palladium(II) complexes were synthesized with bidentate heteroditopic carbene ligands that combine an imidazol-2-ylidene (nNHC) with a 1,2,3-triazol-5-ylidene (tzNHC) connected by a propylene bridge. The silver(I) and gold(I) complexes were dinuclear species, [M2(nNHC-tzNHC)2](PF6)2 (M = Ag or Au), with the two bidentate ligands bridging the metal centers, whereas in the palladium(II) complex [Pd(nNHC-tzNHC)2](PF6)2, the two ligands were chelated on the same metal center. Because of the presence of two different carbene units, isomers were observed for the gold(I) and palladium(II) complexes. The molecular structures of the head-to-tail isomer for gold(I) complexes, with a twisted or folded-syn conformation of the bridge between the carbene units, were determined by X-ray diffraction analysis. The study was completed with a systematic structural investigation through density functional theory (DFT) calculations. For palladium(II) species, the head-to-head form was structurally characterized. The dinuclear gold(I) complexes were emissive in the solid state in the blue region (PLQY up to 8%); time-dependent density functional theory (abbreviated as TD-DFT) calculations disclosed that the absorption bands have metal-to-ligand-charge-transfer character and evidenced that the emission occurs from the T1 level (phosphorescence).

Synthesis of alternating metallocopolymers by chiral recognition.

We report the synthesis of chiral enantiopure polytopic bridging ligands, which may lead to the formation of metallosupramolecular polymers with zinc (II) as metal linker. We show that chiral C2 -symmetric bisoxazoline ligands are useful moieties to efficiently generate heterochiral complexes and thus polymeric entities. The corresponding metallopolymers were further characterized by powder X-ray diffraction (PXRD) to obtain information on the level of crystallinity of our different metallopolymers.

N-Heterocyclic Carbene-Platinum Complexes Featuring an Anthracenyl Moiety: Anti-Cancer Activity and DNA Interaction.

A platinum (II) complex stabilized by a pyridine and an N-heterocyclic carbene ligand featuring an anthracenyl moiety was prepared. The compound was fully characterized and its molecular structure was determined by single-crystal X-ray diffraction. The compound demonstrated high in vitro antiproliferative activities against cancer cell lines with IC50 ranging from 10 to 80 nM. The presence of the anthracenyl moiety on the N-heterocyclic carbene (NHC) Pt complex was used as a luminescent tag to probe the metal interaction with the nucleobases of the DNA through a pyridine-nucleobase ligand exchange. Such interaction of the platinum complex with DNA was corroborated by optical tweezers techniques and liquid phase atomic force microscopy (AFM). The results revealed a two-state interaction between the platinum complex and the DNA strands. This two-state behavior was quantified from the different experiments due to contour length variations. At 24 h incubation, the stretching curves revealed multiple structural breakages, and AFM imaging revealed a highly compact and dense structure of platinum complexes bridging the DNA strands.

Easy Ruthenium-Catalysed Oxidation of Primary Amines to Nitriles under Oxidant-Free Conditions.

A dehydrogenation of primary amine to give the corresponding nitrile under oxidant- and base-free conditions catalysed by simple [Ru(p-cym)Cl2 ]2 with no extra ligand is reported. The system is highly selective for alkyl amines, whereas benzylamine derivatives gave the nitrile product together with the imine in a ratio ranging from 14:1 to 4:1 depending on the substrate. Preliminary mechanistic investigations have been performed to identify the key factors that govern the selectivity.