Bifunctional Complex Research Articles

Cryo-EM structure of the bifunctional secretin complex of Thermus thermophilus.

Secretins form multimeric channels across the outer membrane of Gram-negative bacteria that mediate the import or export of substrates and/or extrusion of type IV pili. The secretin complex of Thermus thermophilus is an oligomer of the 757-residue PilQ protein, essential for DNA uptake and pilus extrusion. Here, we present the cryo-EM structure of this bifunctional complex at a resolution of ~7 Å using a new reconstruction protocol. Thirteen protomers form a large periplasmic domain of six stacked rings and a secretin domain in the outer membrane. A homology model of the PilQ protein was fitted into the cryo-EM map. A crown-like structure outside the outer membrane capping the secretin was found not to be part of PilQ. Mutations in the secretin domain disrupted the crown and abolished DNA uptake, suggesting a central role of the crown in natural transformation.

Nitrogen-Carbon Bond Formation by Reactions of a Titanium-Potassium Dinitrogen Complex with Carbon Dioxide, tert-Butyl Isocyanate, and Phenylallene.

Nitrogen-carbon bond-forming reactions at coordinated dinitrogen in a bifunctional titanium-potassium system are reported. A titanium atrane complex with a tris(aryloxide)methyl ligand (1) was treated with two equivalents of potassium naphthalenide under N2 atmosphere to generate a bifunctional complex (2) in which N2 binds end-on to two titanium centers and side-on to three potassium cations. Dinitrogen complex 2 reacted with carbon dioxide, tert-butyl isocyanate, and phenylallene, forming nitrogen-carbon bonds and affording diverse N-functionalized products. The reaction of 2 with CO2 followed by addition of Me3 SiCl resulted in the formation of the starting complex 1 with concomitant release of silylated carboxyl hydrazines while the reaction with two equivalents of tert-butyl isocyanate proceeded by insertion into the Ti-N bonds. Treatment of 2 with phenylallene afforded vinyl-substituted hydrazido complexes.

Nitrogen–Carbon Bond Formation by Reactions of a Titanium–Potassium Dinitrogen Complex with Carbon Dioxide, tert‐Butyl Isocyanate, and Phenylallene

AbstractNitrogen–carbon bond‐forming reactions at coordinated dinitrogen in a bifunctional titanium–potassium system are reported. A titanium atrane complex with a tris(aryloxide)methyl ligand (1) was treated with two equivalents of potassium naphthalenide under N2 atmosphere to generate a bifunctional complex (2) in which N2 binds end‐on to two titanium centers and side‐on to three potassium cations. Dinitrogen complex 2 reacted with carbon dioxide, tert‐butyl isocyanate, and phenylallene, forming nitrogen–carbon bonds and affording diverse N‐functionalized products. The reaction of 2 with CO2 followed by addition of Me3SiCl resulted in the formation of the starting complex 1 with concomitant release of silylated carboxyl hydrazines while the reaction with two equivalents of tert‐butyl isocyanate proceeded by insertion into the Ti−N bonds. Treatment of 2 with phenylallene afforded vinyl‐substituted hydrazido complexes.

Acceptorless Alcohol Dehydrogenation: OH vs NH Effect in Bifunctional NHC–Ir(III) Complexes

Bifunctional complexes bearing N-heterocyclic carbene (NHC) ligands functionalized with hydroxy or amine groups were synthesized to measure the beneficial effect of different modes of metal–ligand cooperation in the acceptorless dehydrogenation of alcohols. In comparison to complexes with an amine moiety, hydroxy-functionalized iridium catalysts showed superior activity. In contrast to alcohols, 1,4-diols underwent cyclization to give the corresponding tetrahydrofurans without involving dehydrogenation processes. Mechanistic investigations to rationalize the “OH effect” in these types of complexes have been undertaken.

ChemInform Abstract: Advantageous Asymmetric Ketone Reduction with a Competitive Hydrogenation/Transfer Hydrogenation System Using Chiral Bifunctional Iridium Catalysts.

Hydrogenation of aromatic ketones with chiral bifunctional amidoiridium complexes proceeds in preference to transfer hydrogenation in methanol, in which the pressurised hydrogen can suppress unintended racemisation of the alcoholic product, leading to enhanced enantioselectivity.

Opposite Rotation Directions in the Synthesis and Hydrolysis of ATP by the ATP Synthase: Hints from a Subunit Asymmetry

The ATP synthase can be imagined as a reversible H(+)-translocating channel embedded in the membrane, FO portion, coupled to a protruding catalytic portion, F1. Under physiological conditions the F1FO complex synthesizes ATP by exploiting the transmembrane electrochemical gradient of protons and their downhill movement. Alternatively, under other patho-physiological conditions it exploits ATP hydrolysis to energize the membrane by uphill pumping protons. The reversibility of the mechanism is guaranteed by the structural coupling between the hydrophilic F1 and the hydrophobic FO. Which of the two opposite processes wins in the energy-transducing membrane complex depends on the thermodynamic balance between the protonmotive force (Δp) and the phosphorylation potential of ATP (ΔG P). Accordingly, while Δp prevalence drives ATP synthesis by translocating protons from the membrane P-side to the N-side and generating anticlockwise torque rotation (viewed from the matrix), ΔG P drives ATP hydrolysis by chemomechanical coupling of FO to F1 with clockwise torque. The direction of rotation is the same in all the ATP synthases, due to the conserved steric arrangement of the chiral a subunit of FO. The ability of this coupled bi-functional complex to produce opposite rotations in ATP synthesis and hydrolysis is explained on the basis of the a subunit asymmetry.

The a subunit asymmetry dictates the two opposite rotation directions in the synthesis and hydrolysis of ATP by the mitochondrial ATP synthase

The main and best known role of the mitochondrial ATP synthase is to synthesize ATP by exploiting the transmembrane electrochemical gradient of protons and their downhill movement. However, under different conditions, the same enzyme can also switch to the opposite function of ATP hydrolysis and exploits its energy to pump protons against their gradient and energize the membrane. The change in functionality is linked to the change of direction of rotation of the two matched sectors of this unique complex, namely the hydrophilic F1, which performs the catalysis, and the hydrophobic membrane-embedded FO, which channels protons. Accordingly, viewed from the matrix side, ATP synthesis is driven by counterclockwise rotation and ATP hydrolysis by clockwise rotation of the FO rotor which is transmitted to F1. ATP dissipation through this mechanism features some diseases such as myocardial ischemia. Increasing evidence shoulders the hypothesis that the asymmetry of the a subunit of FO and particularly the steric arrangement of the two inner semi-channels for protons, play a key role in conferring to the coupled bi-functional complex the ability to reverse rotation by switching from ATP synthesis to ATP hydrolysis and vice versa. Accordingly, the conserved steric arrangement of the chiral a subunit of FO yields the same direction of rotation for all the ATP synthases. According to this hypothesis, the a subunit chirality imposes the direction of rotation of the rotor according to the proton gradient across the membrane. It seems likely that the direction of rotation of the membrane-embedded c-ring, which is adjacent to the a-subunit and acts as a rotor, may be under multiple control, being rotation essential to make the whole enzyme machinery work. However, the asymmetric features of the a subunit would make it the master regulator, thus directly determining which of the two functions, ATP production or ATP dissipation, will be performed. The handedness of a subunit should be considered in drug design to counteract tissue damage under all pathological conditions linked to functional impairment of ATP synthase.

Synthesis of Fe–H/Si–H and Fe–H/Ge–H Bifunctional Complexes and Their Catalytic Hydrogenation Reactions toward Nonpolar Unsaturated Organic Molecules

The iron hydride complexes bearing a Si–H or a Ge–H functional group in a ligand [2,5-SiPh3-3,4-butylene-(η5-C4COEEt2H)]Fe(CO)2H (E = Si (4), Ge (5)) and [2,5-SiPh3-3,4-butylene-(η5-C4COSiMe2OSiMe2H)]Fe(CO)2H (6), were synthesized in the reaction of the iron acetonitrile complex [2,5-SiPh3-3,4-butylene-(η4-C4CO)]Fe(CO)2(NCCH3) (3) with Et2EH2 or HSiMe2OSiMe2H. These complexes did not hydrogenate a polar unsaturated bond in either ketones or aldehydes but did hydrogenate a nonpolar unsaturated bond in alkynes and alkenes to give alkenes and alkanes selectively. These complexes also catalyzed a transfer hydrogenation reaction from isopropyl alcohol (IPA) to alkynes and alkenes.

ChemInform Abstract: Bifunctional Iron Complexes: Efficient Catalysts for C=O and C=N Reduction in Water.

ChemInform Abstract: Bifunctional Iron Complexes: Efficient Catalysts for C=O and C=N Reduction in Water.

Anticancer Activity and DNA Binding of a Bifunctional Ru(II) Arene Aqua-Complex with the 2,4-Diamino-6-(2-pyridyl)-1,3,5-triazine Ligand

The synthesis and full characterization of the new aqua-complex [(η(6)-p-cymene)Ru(OH2)(κ(2)-N,N-2-pydaT)](BF4)2, [2](BF4)2, and the nucleobase derivative [(η(6)-p-cymene)Ru(9-MeG)(κ(2)-N,N-2-pydaT)](BF4)2, [4](PF6)2, where 2-pydaT = 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine and 9-MeG = 9-methylguanine, are reported here. The crystal structures of both [4](PF6)2 and the chloro complex [(η(6)-p-cymene)RuCl(κ(2)-N,N-2-pydaT)](PF6), [1](PF6), have been elucidated by X-ray diffraction. The former provided relevant information regarding the interaction of the metallic fragment [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) and a simple model of DNA. NMR and kinetic absorbance studies have proven that the aqua-complex [2](BF4)2 binds to the N7 site of guanine in nucleobases, nucleotides, or DNA. A stable bifunctional interaction (covalent and partially intercalated) between the [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) fragment and CT-DNA has been corroborated by kinetic, circular dichroism, viscometry, and thermal denaturation experiments. The reaction mechanism entails the very fast formation of the Ru-O-(PO3) linkage prior to the fast intercalation of the 2-pydaT fragment. Then, a Ru-N7-(G) covalent bond is formed at the expense of the Ru-O-(PO3) bond, yielding a bifunctional complex. The dissociation rate of the intercalated fragment is slow, and this confers additional interest to [2](BF4)2 in view of the likely correlation between slow dissociation and biological activity, on the assumption that DNA is the only biotarget. Furthermore, [2](BF4)2 displays notable pH-dependent cytotoxic activity in human ovarian carcinoma cells (A2780, IC50 = 11.0 μM at pH = 7.4; IC50 = 6.58 μM at pH = 6.5). What is more, complex [2](BF4)2 is not cross-resistant with cisplatin, exhibiting a resistance factor, RF(A2780cis), of 0.28, and it shows moderate selectivity toward the cancer cell lines, in particular, A2780cis (IC50 = 3.0 5 ± 0.08 μM), relative to human lung fibroblast cells (MRC-5; IC50 = 24 μM), the model for healthy cells.

Nanocomposites based on layered silicates and ultrahigh-molecular-mass polyethylene prepared via in situ polymerization

Nanocomposites based on ultrahigh-molecular-mass PE and layered silicates are prepared via in situ polymerization. The process is conducted in the suspension mode under mild conditions with the use of a conventional Ziegler-Natta catalyst and a bifunctional complex containing a nickel oligoallene component along with a titanium component. The fillers are four types of montmorillonite: nonmodified montmorillonite and three montmorillonites modified with various organic intercalants. In their presence, the activities of the catalysts appreciably increase (by a factor of 2–3). Composites containing 10–40 wt % aluminosilicates are prepared. The structures of the polymer matrix and composites are studied via X-ray diffraction. It is found that the degree of exfoliation of the filler depends not only on its amount but also on the type of modifier and the type of catalytic system. The PE matrix with a molecular mass of (1.5–1.6) × 106 has a melting point of T m = 141–143°C, a high enthalpy of melting, and a high degree of crystallinity. The IR-spectral studies of the polymers synthesized with the bifunctional complex reveal the presence of branches in a chain, thereby suggesting the formation of linear PE with a medium density (0.938–0.946 g/cm3). Nanocomposites containing 10% aluminosilicate possess the best complex of mechanical properties relative to that of unfilled polyethylene.

Organosilylated Complex [Eu(TTA)3(Bpy-Si)]: A Bifunctional Moiety for the Engeneering of Luminescent Silica-Based Nanoparticles for Bioimaging

A new highly luminescent europium complex with the formula [Eu(TTA)3(Bpy-Si)], where TTA stands for the thenoyltrifluoroacetone, (C4H3S)COCH2COCF3, chelating ligand and Bpy-Si, Bpy-CH2NH(CH2)3Si(OEt)3, is an organosilyldipyridine ligand displaying a triethoxysilyl group as a grafting function has been synthesized and fully characterized. This bifunctional complex has been grafted onto the surface of dense silica nanoparticles (NPs) and on mesoporous silica microparticles as well. The covalent bonding of [Eu(TTA)3(Bpy-Si)] inside uniform Stöber silica nanoparticles was also achieved. The general methodology proposed could be applied to any silica matrix, allowed high grafting ratios that overcome chelate release and the tendency to agglomerate. Luminescent silica-based nanoparticles SiO2-[Eu(TTA)3(Bpy-Si)], with a diameter of 28 ± 2 nm, were successfully tested as a luminescent labels for the imaging of Pseudomonas aeruginosa biofilms. They were also functionalized by a specific monoclonal antibody and subsequently employed for the selective imaging of Escherichia coli bacteria.

Abstract 3427: The dinuclear platinum agent, BBR3610-DACH, exhibits a significant anti-proliferative effect: Regulation of G1/S and G2/M cell cycle arrest and apoptosis induction.

Abstract BBR3610-DACH, a long-chain, bifunctional dinuclear PTII complex with a similar DNA binding mode to the Phase II clinical drug, BBR3464 and its potent analogue, BBR3610, was shown previously to be resistant to metabolic decomposition by sulfur-containing nucleophiles. Initial observations utilizing the alkaline comet assay indicate that BBR3610-DACH forms interstrand crosslinks. Cell cycle analysis using flow cytometry showed that BBR3610-DACH inhibited cell proliferation and caused G1/S and G2/M cell cycle arrest in HCT116 colorectal cells in a time dependent manner accompanied with significant s phase depletion. Similar experiments with synchronized cells showed a distinct G1 phase arrest elicited by the drug following release from arrest. Immunoblotting revealed a stabilization of p53 between 6-24hr after treatment with 20μM (IC90) BBR3610-DACH, with a concomitant increased levels of the cyclin dependent kinase inhibitors, p21 and p27. Cell proliferation assay using MTT and subsequent cell cycle studies with HCT116 p53-/- and HCT116 p21-/- indicated that the cytotoxicity profile of BBR3610-DACH was p21 dependent and partially dependent on the p53 status. However, no change was observed in the protein levels of cyclin E, CDK2, and CDC25A which are G1 phase regulators. Decrease in the levels of cyclin A and cyclin B1 at 24hrs suggested a G2/M block indicative of a possible mitotic catastrophe. Next, we examined whether the DNA damage sensor protein kinases, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and RAD3 related (ATR) had a role in the cell cycle regulation after drug treatment. Studies using the ATM inhibitor, KU-60019 and caffeine (inhibits both ATM and ATR) revealed no apparent role of ATM but a possible dependence on ATR. Following the cell cycle effects, BBR3610-DACH induced cell death as seen from cleaved poly (ADP-ribose) polymerase-1 (PARP-1) levels as early as 6hrs after drug treatment. Interestingly, no cleaved caspase 3 was seen suggesting a caspase-independent PARP cleavage. Together these findings suggest that BBR3610-DACH is a major cell cycle inhibitory DNA binding platinum agent that could be further developed as a major chemotherapeutic. Citation Format: Vijay Menon, Erica Peterson, Sumitra Deb, Lawrence Povirk, Nicholas Farrell. The dinuclear platinum agent, BBR3610-DACH, exhibits a significant anti-proliferative effect: Regulation of G1/S and G2/M cell cycle arrest and apoptosis induction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3427. doi:10.1158/1538-7445.AM2013-3427

Toxicity in tumor cells, DNA binding mode, and resistance to decomposition by sulfur nucleophiles of new dinuclear bifunctional trans-PtII complexes containing long alkane linkers

In an effort to design dinuclear PtII compounds that maintain the target (DNA) binding profile of the trans-oriented dinuclear bifunctional PtII complexes containing aliphatic linker chains but are less susceptible to metabolic decomposition, the new, long-chain dinuclear PtII complexes—[{trans-PtCl(dien)}2-μ-(CH2) n ]2+ (n = 7,10,12, dien = diethylenetriamine)—were synthesized. The toxicity of these metallodrugs was examined in ovarian tumor cell lines. The results showed that the activity of these complexes increased with growing length of the linker; the activity of complex containing the longest linker (n = 12) was comparable with that of cis-diamminedichloridoplatinum(II) (cisplatin). This observation correlated with the results of DNA binding studies performed in cell-free media. The results of these studies demonstrated that the growing length of the aliphatic bridge promoted more distorting conformational alterations induced in DNA. Attention was also paid to the reactivity of {[Pt(dien)Cl]2-alkane} compounds with glutathione (GSH). The results of these experiments support the thesis that the dinuclear structure of {[Pt(dien)Cl]2-alkane} complexes remains stable in the presence of S-containing compounds without undergoing chemical degradation as previously observed for some di/trinuclear bifunctional PtII complexes. This enhanced stability represents a favorable property which may contribute to reduce side effects and increase therapeutic efficacy of the dinuclear {[Pt(dien)Cl]2-alkane} compounds.

Determination of ammonia-oxidizing bacteria based on time-resolved fluorescence and tandem probe

To study the ecology of ammonia-oxidizing bacteria (AOB), quantitative techniques are essential. In this report, the authors introduced an innovative method based on time-resolved fluorescence to quantify AOB as a representative of the major functional microorganisms in sewage water treatment. A bifunctional europium complex with the characteristics of long lifetime and intense luminescence was used as labels in the experiments. In the detection, the capture probe and dye-labeled reporter probe could form a two-probe tandem with the target sequence, and the determination of target DNA was done by monitoring the time-resolved fluorescence signals of europium complex-labeled reporter probe left on the glass slide surface. The experiment conditions consisting of concentration of capture probe, hybridization temperature, hybridization time and washing time were optimized. This method presents satisfactory specificity to common bacteria such as Nitrobacter winogradskyi, Escherichia coli and Paenibacillus polymyxa. The detection limit was 3.65 × 10(-11)mol L(-1). This detection system enables us to rapidly and sensitively analyze the microbial population variety in sewage water treatment.

Novel CaO–SiO2 Sorbent and Bifunctional Ni/Co–CaO/SiO2 Complex for Selective H2 Synthesis from Cellulose

Catalysis- and sorption-enhanced biomass gasification is a promising route to high-purity hydrogen (H(2)); however, most CaO-based sorbents for CO(2) capture have poor surface area and mechanical properties, lose carrying capacity over multiple uses, and have insufficient porosity to accommodate extra catalyst sites. We aimed to develop a high-surface-area CaO-SiO(2) framework onto which catalysts could be grafted. The best CaO-SiO(2) sorbent (n(Ca)/n(Si) = 2:1) maintained a CaO conversion of 65% even after 50 carbonation-decarbonation cycles, better than commercial micrometer-sized CaO or tailored CaO, because of stabilization via Ca-O-Si interactions and an ordered porous structure. Bimetallic catalyst grains (Ni/Co alloy, <20 nm) could be evenly loaded onto this structure by impregnation. The resulting bifunctional complex produced H(2) at nearly the same rate as a mixture of catalyst and commercial CaO while using less total sorbent/catalyst. Furthermore, this complex was much more durable due to its higher coking resistance and stable structure. After 25 carbonation-decarbonation cycles, the new catalyst-sorbent complex enhanced the H(2) yield from cellulose far more than a mixture of catalyst and commercial CaO did following the same treatment.

Preparation of Organometallic Ruthenium–Arene–Diaminotriazine Complexes as Binding Agents to DNA

The reactions of two diaminotriazine ligands 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine (2-pydaT) and 6-phenyl-2,4-diamino-1,3,5-triazine (PhdaT) with ruthenium-arene precursors led to a new family of ruthenium(II) compounds that were spectroscopically characterized. Four of the complexes were cationic, with the general formula [(η(6)-arene)Ru(κ(2)-N,N-2-pydaT)Cl]X (X=BF(4), TsO; arene=p-cymene: 1·BF(4), 1·TsO; arene=benzene: 2·BF(4), 2·TsO). The neutral cyclometalated complex [(η(6)-p-cymene)Ru(κ(2)-C,N-PhdaT*)Cl] (3) was also isolated. The structures of complexes 2·BF(4) and 3·H(2)O were determined by X-ray diffraction. Complex 1·BF(4) underwent a partial reversible-aquation process in water. UV/Vis and NMR spectroscopic measurements showed that the reaction was hindered by the addition of NaCl and was pH-controlled in acidic solution. At pH 7.0 (sodium cacodylate) Ru-Cl complex 1·BF(4) was the only species present in solution, even at low ionic strength. However, in alkaline medium (KOH), complex 1·BF(4) underwent basic hydrolysis to afford a Ru-OH complex (5). Fluorimetric studies revealed that the interaction of complex 1·BF(4) with DNA was not straightforward; instead, its main features were closely linked to ionic strength and to the [DNA]/complex ratio. The bifunctional complex 1·BF(4) was capable of interacting concurrently through both its p-cymene and 2-pydaT groups. Cytotoxicity and genotoxicity studies showed that, contrary to the expected behavior, the complex species was biologically inactive; the formation of a Ru-OH complex could be responsible for such behavior.

Kinetics and mechanism of the reactions of Au(iii) complexes with some biologically relevant molecules

The kinetics of the substitution reactions between the mono-functional Au(III) complexes, [Au(dien)Cl](2+) and [Au(terpy)Cl](2+) (dien = 3-azapentane-1,5-diamine, terpy = 2,2';6',2''-terpyridine) and bi-functional Au(III) complexes, [Au(bipy)Cl(2)](+) and [Au(dach)Cl(2)](+) (bipy = 2.2'-bipyridine, dach = (1R,2R)-1,2-diaminocyclohexane) and biologically relevant ligands such as l-histidine (l-His), inosine (Ino), inosine-5'-monophosphate (5'-IMP) and guanosine-5'-monophosphate (5'-GMP), were studied in detail. All kinetic studies were performed in 25 mM Hepes buffer (pH = 7.2) in the presence of NaCl to prevent the spontaneous hydrolysis of the chloride complexes. The reactions were followed under pseudo-first order conditions as a function of ligand concentration and temperature using stopped-flow UV-vis spectrophotometry. The results showed that the mono-functional complexes react faster than the bi-functional complexes in all studied reactions. The [Au(terpy)Cl](2+) complex is more reactive than the [Au(dien)Cl](2+) complex, which was confirmed by quantum chemical (DFT) calculations. A more than 50% lower activation energy for the terpy than for the dien based complex was found. The bi-functional [Au(bipy)Cl(2)](+) complex is more reactive than the [Au(dach)Cl(2)](+) complex. The reactivity of the studied nucleophiles follows the same order for all studied systems, viz. l-His > 5'-GMP > 5'-IMP > Ino. According to the measured activation parameters, all studied reactions follow an associative substitution mechanism. Quantum chemical calculations (B3LYP/LANL2DZp) suggest that ligand substitution in [Au(terpy)Cl](2+) and [Au(dien)Cl](2+) by imidazole follows an interchange mechanism with a significant degree of associative character. The results demonstrate the strong connection between the reactivity of the complexes toward biologically relevant ligands and their structural and electronic characteristics. Therefore, the binding of gold(III) complexes to 5'-GMP, constituent of DNA, is of particular interest since this interaction is thought to be responsible for their anti-tumour activity.

Enantioselective Synthesis of Chiral Propargylic Alcohols Catalyzed by Bifunctional Zinc-Based Complexes

This work demonstrates an efficient way to prepare chiral propargylic alcohols by asymmetric addition of terminal Zn-acetylide to aldehydes catalyzed by bifunctional zinc-based complexes. The corresponding products with moderate to good yields and enantioselectivities were obtained in the absence of moisture-sensitive Ti(O i Pr)4.

Evaluation of Platinum–Ethacrynic Acid Conjugates in the Treatment of Mesothelioma

Malignant pleural mesothelioma (MPM) cells are characterized by chemoresistance associated with glutathione (GSH) metabolism. Ethacrynic acid (EA) is able to inhibit the detoxifying enzyme glutathione-S-transferase (GST), which catalyzes the conjugation between GSH and Pt-based drugs. With the aim of obtaining active bifunctional drugs, a Pt(II) complex containing two EA moieties as leaving groups, namely cis-diamminobis(ethacrynato)platinum(II), was synthesized, characterized, and tested on four MPM cell lines. The resulting antiproliferative activity was compared with that elicited by the analogue Pt(IV) complex, cis,cis,trans-diamminodichloridobis(ethacrynato)platinum(IV) (ethacraplatin) and by the co-administration of free EA and cisplatin. The Pt(II) and Pt(IV) bifunctional complexes showed poorer performance than the reference drug cisplatin alone or in combination with EA. After treatment, cellular GST activity remained consistently unchanged, while the GSH level increased.