N-heterocyclic Carbene Platinum Research Articles

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.

A green route to platinum N-heterocyclic carbene complexes: mechanism and expanded scope.

A sustainable and facile weak-base synthetic route to platinum N-heterocyclic carbene (NHC) complexes is disclosed. The mechanism of this reaction is also elucidated via experimental and computational investigations. This straightforward protocol is then used for the synthesis of novel Pt(II)-NHC complexes and its utility is further explored to access key Pt(0)-NHC precatalysts.

Concentration Effect in Surface Plasmon-Coupled Phosphorescence (SPCP) Emission Engineering with Augmented S-Polarization from N-Heterocyclic Carbene Platinum(II) Complexes

Concentration Effect in Surface Plasmon-Coupled Phosphorescence (SPCP) Emission Engineering with Augmented S-Polarization from N-Heterocyclic Carbene Platinum(II) Complexes

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).

Synthesis, Characterization, and Catalytic Activity of Chiral NHC Platinum(II) Pyridine Dihalide Complexes

A series of platinum(II) dihalide pyridine complexes bearing chiral C2-symmetric N-heterocyclic carbene (NHC) ligands [Pt(NHC*)(Py)(Hal)2] was synthesized in a one-pot procedure and characterized b...

Synthesis and structural characterization of benzyl-functionalized N-heterocyclic carbene platinum complexes: Dramatic substituent effect on anti-cancer activity

A series of platinum (II) complexes bearing N-heterocyclic carbene NHC ligands functionalized by various benzyl moieties were synthesized and characterized. The molecular structure of two complexes has been confirmed by X-ray diffraction studies on single crystals. Investigation of in vitro cytotoxic activities against various cancer cell lines revealed a strong substituent effect: IC50 as low as 0.005 μM were obtained depending on the substituent on the benzyl moiety.

Synthesis, characterization, in vitro antimicrobial and anticancer studies of new platinum N-heterocyclic carbene (NHC) complexes and unexpected nickel complexes

A series of bidendate pyridine-functionalized metal N-heterocyclic carbene (NHC) complexes with various wingtip substituents (R = methyl, phenyl and tert-butyl) had been prepared from silver oxide-mediated transmetalation method. The basic backbone of the NHC ligands were prepared in two stepwise reactions: reduction of the commercially available 2-benzoylpyridine, followed by halogenation to yield 2-(chloro(phenyl)methyl)pyridine. Subsequent reactions with different imidazoles gave the desired imidazolium salts (or NHC precursors) with different R groups at the N wingtip (R = Me, Ph, t-Bu). Transmetalation of the imidazolium salts into platinum NHC complexes were achieved by using Ag2O mediated method with Pt(cod)Cl2 as the transmetalating agent. On the other hand, nickel NHC complexes were obtained via one pot synthesis method with nickel chloride as the transmetalating agent and reflux in the presence of a base. Following recrystallisation, the molecular structure of Pt NHC complex ( ± )-5a had been successfully elucidated via single crystal X ray diffraction (XRD) analysis. The six-membered ring of the platinum NHC complexes adopted a boat conformation with the phenyl ring arranged at the axial position. Meanwhile, two unexpected nickel complexes, i.e. a simple nickel coordination complex and a nickelate complex, were obtained and studied using XRD. These Pt NHC complexes and unexpected Ni complexes were evaluated for their in vitro antimicrobial and anticancer activities against a panel of pathogenic microorganisms and three selected human cancer cell lines, including breast (MCF7), colon (HCT116) and oral (H103) cancer cells. Generally, the Pt NHC complexes displayed enhanced antimicrobial activities upon coordination to metals, as compared to the corresponding imidazolium salts i.e. NHC precursors, with minimum inhibitory concentration (MIC) values in micromolar (μM) range. A couple of platinum NHC complexes synthesized exhibited antimicrobial activities with MIC as low as 2 μM, which are comparable to silver NHC complexes with renowned antimicrobial profiles. Similarly, upon coordination to the metals, the cytotoxic effects of the platinum NHC complexes increased significantly as compared to the imidazolium salts. Among all, platinum NHC complex (±)-5c displayed significant cytotoxicities towards the cancer cells with IC50 values that are two to three times lower than that of the anticancer drug cisplatin. In summary, evidences for influence of both wingtip substituents and metals on the biological activities of the complexes have been found.

Synthesis, characterization, and photophysical properties of cyclometalated N-Heterocyclic carbene Platinum(II) complexes

Thiophene and benzothiophene ligands containing N-heterocyclic carbene (NHC) moieties were used to synthesize five and six-membered Pt(II) metallacycles. Ligand scaffolding was synthesized using two methods. The ligands were synthesized using a coupling reaction, utilizing Cu2O as the catalyst or were synthesized using a nucleophilic substitution reaction. The ligands were then metalated by chelate-assisted CH activation. The synthesis, characterization, reactivity, and photophysical properties of these NHC-functionalized, cyclometalated products are reported.

N-heterocyclic carbene platinum complexes functionalized with a polyether chain and silyl group: Synthesis and application as a catalyst for hydrosilylation

GRAPHICAL ABSTRACT

Synthesis of N-Heterocyclic Carbene Platinum Complexes and Application in the Organic Reaction

Synthesis of N-Heterocyclic Carbene Platinum Complexes and Application in the Organic Reaction

N-Heterocyclic Carbene-Polyethylenimine Platinum Complexes with Potent in Vitro and in Vivo Antitumor Efficacy.

The current interest for platinum N-heterocyclic carbene complexes in cancer research stems from their impressive toxicity reported against a range of different human cancer cells. To date, the demonstration of their in vivo efficacy relative to that of established platinum-based drugs has not been specifically addressed. Here, we introduce an innovative approach to increase the NHC-Pt complex potency whereby multiple NHC-Pt(II) complexes are coordinated along a polyethylenimine polymer (PEI) chain. We show that such NHC-Pt(II)-PEI conjugates induce human cancer cell death in vitro and in vivo in a xenograft mouse model with no observable side effects in contrast to oxaliplatin. Additional studies indicate nucleus and mitochondria targeting and suggest various mechanisms of action compared to classical platinum-based anticancer drugs.

User-Friendly Platinum Catalysts for the Highly Stereoselective Hydrosilylation of Alkynes and Alkenes.

With a view to addressing the shortcomings of traditional catalysts, a new generation of outstanding N-heterocyclic carbene platinum(0) complexes for the hydrosilylation of unsaturated carbon-carbon bonds is reported. Their discovery and application to the stereoselective addition of various silanes to silylated alkynes, terminal acetylenes, and olefins is presented. Insights into the catalytic cycle and the origin of the stereoselectivity are also discussed.

Synthesis, structural characterization and in vitro anti-cancer activity of functionalized N-heterocyclic carbene platinum and palladium complexes

A series of platinum(II) and palladium(II) complexes bearing N-heterocyclic carbene ligands functionalized by specific functionalities such as alcohol, nitrile or ester were synthesized. The novel complexes were fully characterized and X-ray diffraction was used for the structure determination of eight derivatives. The reactivity of the functional groups has been studied; for example, Pt and Pd NHC complexes containing tBu ester functions were easily hydrolyzed giving water-soluble NHC complexes. The palladium complex 21 containing dangling COOH group was evaluated in copper-free Sonogashira coupling reaction. In addition, platinum NHC complexes are attractive metal-based systems for the development of anticancer drugs. Preliminary results of the biological effects on various human cancer and non-cancer cells are also reported.

Water-Soluble Mono- and Dimethyl N-Heterocyclic Carbene Platinum(II) Complexes: Synthesis and Reactivity

A family of water-soluble dimethyl complexes of formula cis-[PtMe2(dmso)(NHC·Na)] (2), in which NHC is an anionic N-heterocyclic carbene bearing a sulfonatopropyl chain on one of the nitrogen atoms and a sulfonatopropyl (a), methyl (b), mesityl (c), or 2,6-diisopropylphenyl group (d) on the other, have been prepared. The hydrolytic stability of the Pt–C bonds in these complexes under different neutral, alkaline, and acidic aqueous conditions has also been studied. Complexes 2 were found to be quite stable at room temperature in water under neutral or alkaline conditions. Degradation occurred at higher temperatures but involved C sp3–H activation and C–C reductive elimination processes in addition to Pt–Me bond hydrolysis. Hydrolytic cleavage of the platinum–methyl bonds was favored by good nucleophiles. Thus, the addition of KCN to an aqueous solution of 2 resulted in formation of the monomethyl complexes K[PtMe(CN)2(NHC·Na)] (9), whereas the dimethyl complexes K[PtMe2(CNR)(NHC·Na)] (10) were formed with the isocyanide CNCH2COOK. The addition of stoichiometric amounts of protic acids to aqueous solutions of 2 resulted in the clean cleavage of one or both platinum(II)–methyl bonds. Thus, the reaction of 2 with HCl afforded the complexes [PtClMe(dmso)(NHC·Na)] (3) and [PtCl2(dmso)(NHC·Na)] (4), whereas [PtMe(OH2)(dmso)(NHC)] (5) and [Pt(OH2)2(dmso)(NHC)][BF4] (7) were obtained upon treatment with HBF4. The crystal structure of 9a is remarkable in light of the longitudinal channels around 6 Å in diameter internally decorated with Pt–Me bonds.

Pyridyl- and diphenylphosphinoethyl-functionalised N-heterocyclic carbene platinum methyl complexes

The novel platinum (II) dimethyl complexes Pt(κ2-L1)Me2 and Pt(κ2-L1)Me2 (1), Pt(κ2-L2a)Me2 (2a) and Pt(κ2-L2b)Me2 (2b) bearing the functionalised N-heterocyclic carbenes (NHCs), L1 = 1-(2-diphenylphosphinoethyl)-3-(2,6-diisopropyl-phenyl)-imidazol-2-ylidene, L2a = 1-(2-pyridyl)-3-(2,6-diisopropyl-phenyl)-imidazol-2-ylidene, L2b = 1-(2-(3-picolinyl))-3-(2, 6-diisopropyl-phenyl)-imidazol-2-ylidene, react with the acid [H(Et2O)2+B(ArF)4−], ArF = 3, 5-(CF3)2C6H3, in the presence of various neutral donors (Dn) to give the salts [{Pt(κ2-L)(Me)(Dn)}+{B(ArF)4}−], where Dn occupies specifically the site trans to the P and the CNHC donor atoms of the coordinated ligands L1 and L2a, L2b, respectively. Spectroscopic data give evidence that the same selectivity prevails when other acids are employed. Activation of the Cl–CH2Cl bond by 2b led to [Pt(κ2-L2b)(Me)Cl], while reaction of CH3I with the dimethyl complexes led to isolable [Pt(κ2-L)Me3I] species.

Derivatization of Preformed Platinum N-Heterocyclic Carbene Complexes with Amino Acid and Peptide Ligands and Cytotoxic Activities toward Human Cancer Cells

A simple procedure for the preparation of N-heterocyclic carbene platinum complexes with a nitrogen-based neutral ligand in trans geometry is presented. The lability of a trans pyridine ligand in an N-heterocyclic carbene–Pt(II)–pyridine complex, namely, (3-benzyl-1-methylimidazolylidene)PtI2(pyridine), 2, was probed by a displacement reaction with various nitrogen-based ligands (e.g., amines, hydrazine, amino esters, and peptides) to yield the corresponding complexes, which could be easily isolated by column chromatography. Two representative complexes could be characterized by X-ray crystallographic studies. This strategy allows generating diversity in metallodrug candidates. Preliminary results of the biological effects on various human cancer cells and comparison wih cisplatin are reported.

Water-Soluble N-Heterocyclic Carbene Platinum(0) Complexes: Recyclable Catalysts for the Hydrosilylation of Alkynes in Water at Room Temperature

The synthesis and characterization of new water-soluble platinum(0) complexes bearing sulfonated N-heterocyclic carbene (NHC) and divinyltetramethylsiloxane (dvtms) ligands are described. These complexes, of the general formula (NHC)Pt(dvtms), are active and recyclable catalysts for the hydrosilylation of phenylacetylene and other alkynes at room temperature in water. Our findings indicate that the NHC–Pt(0) bonds are reasonably stable under these catalytic conditions, although hydrolysis is observed at temperatures above 80 °C in pure water.

Sulfur containing platinum(ii) complexes with N-heterocyclic carbene ligands obtained by reactions of a hydrosulfido complex

A hydrosulfido platinum(ii) complex with a chelated N-heterocyclic carbene (NHC) ligand was oxidised with O(2) in the presence of excess hydrogen sulfide, to give a linear tetrasulfido complex, and without hydrogen sulfide, to give a thiosulfato-bridged dinuclear complex. The hydrosulfido complex also reacted with an acetato complex containing the chelating NHC platinum unit to afford a trinuclear platinum complex with two triply bridging sulfido ligands showing an equilibrium in solution between two isomers based on the arrangement of the chelating NHC ligands.

Novel platinum-N-heterocyclic carbene complex is more cardiotoxic than cis-platin in rats

Cis-platin and other platinum complexes are important chemotherapeutic agents useful in the treatment of several cancers. However, therapeutic usage of cis-platin and other platinum complex are limited by their undesirable side effects including cardiotoxicity. In this context, we aimed to compare the damage caused in heart by cis-platin and novel platinum-N-heterocyclic carbene (Pt-NHC) complex. For this purpose, 35 Sprague-Dawley rats were divided randomly into five equal groups (n = 7 for each group). Cis-platin and novel Pt-NHC complex were intraperitoneally administered at a single dose of 5 mg/kg and 10 mg/kg and then sacrificed 10 days after this treatment. The heart tissues were taken from all rats for determination of oxidative and myocardial damage. Cis-platin and novel Pt-NHC complex caused oxidative and histological damage in the heart tissue in a dose-dependent manner (p < 0.05). On the other hand, at the same dose levels, cis-platin caused lower oxidative and histological damage in heart tissue compared to novel Pt-NHC complex. These results suggest that novel Pt-NHC complex is more cardiotoxic than cis-platin.

Water-Induced Changes of Photoluminescence of a Pincer-Type N-Heterocyclic Carbene Platinum(II) Complex

A square-planar Pt(II) complex with a pyridine-based pincer-type N-heterocyclic carbene ligand, [PtII(C∧N∧C)(Cl)]Cl (C∧N∧C = 2,6-bis(1-butylimidazol-2-ylidenyl)pyridine), was synthesized as a new type of emitter and structurally characterized. The complex shows aquachromic photoluminescence in the solid state upon hydration and dehydration.