Structure-activity relationship of anticancer and antiplasmodial gold bis(dithiolene) complexes.

Monoanionic gold bis(dithiolene) complexes were recently shown to display activity against ovarian cancer cells, Gram-positive bacteria, Candida strains and the rodent malaria parasite, P. berghei. To date, only monoanionic gold(III) bis(dithiolene) complexes with a thiazoline backbone substituted with small alkyl chains have been evaluated for biomedical applications. We now analyzed the influence of the length and the hydrophobicity vs. hydrophilicity of these complexes' alkyl chain on their anticancer and antiplasmodial properties. Isomer analogues of these monoanionic gold(III) bis(dithiolene) complexes, this time with a thiazole backbone, were also investigated in order to assess the influence of the nature of the heterocyclic ligand on their overall chemical and biological properties. In this report we present the total synthesis of four novel monoanionic gold(III) bis(dithiolene) complexes with a long alkyl chain and a polyoxygenated (PEG) chain aiming to improve their solubility and biological properties. Our results showed that the complexes with a PEG chain showed promising anticancer and antiplasmodial activities beside improved solubility, a key parameter in drug discovery and development.

Radical and diradical states of bis(molybdenocene dithiolene) complexes.

The synthesis and characterization of two bis(dithiolene) proligands involving heteroatomic linkers such as 1,4-dithiine and dihydro-1,4-disiline between the two protected dithiolene moieties are described. Two bimetallic complexes involving these heteroatomic bridges between two redox active bis(cyclopentadienyl)molybdenum dithiolene moieties have been synthesized and characterized by electrochemistry, spectroelectrochemistry, and their properties rationalized with (TD-)DFT. Cyclic voltammetry experiments show sequential oxidation of the two redox centers with ΔE values between successive one-electron transfers varying according to the nature of the bridge. Depending on the nature of the heteroatomic bridge, the bis-oxidized complexes exhibit either a diradical character with both radicals essentially localized on the metallacycles, or a closed-shell dicationic state.

A Bimetallic Benzene-1,2,4,5-Tetrathiolate (btt) Molybdenocene Complex Cp2 Mo(btt)MoCp2 : Radical and Diradical States.

Benzene-1,2,4,5-tetrathiolate (btt) has been used as a bridging ligand to prepare a redox active (molybdenocene dithiolene)-based bimetallic complex Cp2 Mo(btt)MoCp2 , which exhibits four successive electron transfers up to the tetracation. Spectro-electrochemical investigations together with DFT and TD-DFT calculations evidence that the two electroactive MoS2 C2 metallacycles are electronically coupled in the monocationic as in the dicationic state. Two salts of the dication [Cp2 Mo(btt)MoCp2 ]2+ have been structurally characterized with PF6 - and HSO4 - counterions, showing different chair or boat conformations associated with variable folding angles of the two MoS2 C2 metallacycles along the S-S hinge. The bis-oxidized dicationic complex exhibits a diradical character, with both radicals essentially localized on the metallacycles and with antiferromagnetic coupling evidenced from magnetic susceptibility measurements.

A highly conducting mixed-valence nickel bis(dithiolene) salt [Et4N][Ni(Me-thiazSe-dt)2]2 with selone substitution.

The prototypical [Ni(dmit)2] complex (dmit: 1,3-dithiole-2-thione-4,5-dithiolate) is modified here by combining the N-R substitution found in [Ni(R-thiazdt)2] complexes (R-thiazdt: N-alkyl-thiazoline-2-thione-4,5-dithiolate) and the selone substitution found in [Ni(dmiSe)2] complex (dmiSe: 1,3-dithiole-2-selone-4,5-dithiolate) to give a novel N-methyl substituted, radical anionic complex formulated as [Ni(Me-thiazSe-dt)2]1- (Me-thiazSe-dt: N-methyl-thiazoline-2-selone-4,5-dithiolate). Both this anionic complex and its mixed-valence Et4N+ salt crystallize with a rare cis arrangement of the two dithiolene ligands around the Ni atom. In the 1 : 2 [Et4N][Ni(Me-thiazSe-dt)2]2 salt, the complexes organize into dimerized chains well isolated from each other, giving the salt a strong one-dimensional character. It shows however a high RT conductivity of 4.6 S cm-1 and small activation energy of 33 meV, indicating a possible Mott insulator behavior, which is not suppressed under pressures up to 10 GPa.

Block Copolymer Micelles Encapsulating Au(III) Bis(Dithiolene) Complexes as Promising Nanostructures with Antiplasmodial Activity.

Block copolymer micelles (BCMs) can be used to improve the solubility of lipophilic drugs and increase their circulation half-life. Hence, BCMs assembled from MePEG-b-PCL were evaluated as drug delivery systems of gold(III) bis(dithiolene) complexes (herein AuS and AuSe) to be employed as antiplasmodial drugs. These complexes exhibited remarkable antiplasmodial activity against liver stages of the Plasmodiumberghei parasite, and low toxicity in a model of zebrafish embryos. To improve the complexes' solubility, BCMs were loaded with AuS, AuSe, and the reference drug primaquine (PQ). PQ-BCMs (Dh = 50.9 ± 2.8 nm), AuSe-BCMs (Dh = 87.1 ± 9.7 nm), and AuS-BCMs (Dh = 72.8 ± 3.1 nm) were obtained with a loading efficiency of 82.5%, 55.5%, and 77.4%, respectively. HPLC analysis and UV-Vis spectrophotometry showed that the compounds did not suffer degradation after encapsulation in BCMs. In vitro release studies suggest that AuS/AuSe-BCMs present a more controlled release compared with PQ-loaded BCMs. The antiplasmodial hepatic activity of the drugs was assessed in vitro and results indicate that both complexes present higher inhibitory activity than PQ, although encapsulated AuS and AuSe presented lower activity than their non-encapsulated counterparts. Nevertheless, these results suggest that the use of BCMs as delivery vehicles for lipophilic metallodrugs, particularly AuS and AuSe, could enable the controlled release of complexes and improve their biocompatibility, constituting a promising alternative to conventional antimalarial treatments.

Mixed-Valence Conductors from Ni Bis(diselenolene) Complexes with a Thiazoline Backbone.

Highly conducting, mixed-valence, multi-component nickel bis(diselenolene) salts were obtained by electrocrystallization of the monoanionic species [Ni(Me-thiazds)2]-1 (Me-thiazds: N-methyl-1,3-thiazoline-2-thione-4,5-diselenolate), with 1:2 and 1:3 stoichiometries depending of the counter ion used (Et4N+ and nBu4N+ vs Ph4P+, respectively). This behavior strongly differs from that of the corresponding monoanionic dithiolene complexes whose oxidation afforded the single component neutral species. This provides additional rare examples of mixed-valence conducting salts of nickel diselenolene complexes, only known in two examples with the dsit (1,3-dithiole-2-thione-4,5-diselenolate) and dsise (1,3-dithiole-2-selone-4,5-diselenolate) ligands. The mixed-valence salts form highly dimerized or trimerized bi- and trimetallic units, rarely seen with such nickel complexes. Transport measurements under a high pressure (up to 10 GPa) and band structure calculations confirm the semiconducting character of [Ph4P][Ni(Me-thiazds)2]3 and the quasi metallic character of [Et4N][Ni(Me-thiazds)2]2 and [NBu4]x[Ni(Me-thiazds)2]2 salts (0 < x < 1).

Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes.

The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)2) and the counter-ion (Ph4P+ or Et4N+). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC50 values ranged from 0.1-8 µM (A2780) and 0.8-29 µM (OVCAR8). The complexes with the Ph4P+ ([P]) counter-ion are in general more active than their Et4N+ ([N]) analogues, presenting IC50 values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with [P] counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)2) enhanced the compounds toxicity. Most complexes containing the [P] counter ion exhibited exceptional antiplasmodial activity against the Plasmodium berghei parasite liver stages, with submicromolar IC50 values ranging from 400-700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the [N] counter-ion. Auranofin and two selected complexes [P][AuSBu(=S)] and [P][AuSEt(=S)] did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes [P] [AuSBu(=S)], [P] [AuSEt(=S)], [P] [AuSEt(=Se)] and [P] [AuSeiPr(=S)] displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability.

Introducing Selenium in Single-Component Molecular Conductors Based on Nickel Bis(dithiolene) Complexes.

Two selenated analogues of the all-sulfur single-component molecular conductor [Ni(Et-thiazdt)2] (Et-thiazdt = N-ethylthiazoline-2-thione-4,5-dithiolate) have been prepared from their precursor radical-anion complexes. Replacement of the thione by a selenone moiety gives the neutral [Ni(Et-thiazSedt)2] complex. It adopts an unprecedented solid-state organization (for neutral nickel complexes), with the formation of perfectly eclipsed dimers and very short intermolecular Se···Se contacts (81% of the van der Waals contact distance). Limited interactions between dimers leads to a large semiconducting gap and low conductivity (σRT = 1.7 × 10-5 S cm-1). On the other hand, going from the neutral [Ni(Et-thiazdt)2] dithiolene complex to the corresponding [Ni(Et-thiazds)2] diselenolene complex gives rise to a more conventional layered structure built out of uniform stacks of the diselenolene complexes, different, however, from the all-sulfur analogue [Ni(Et-thiazdt)2]. Band structure calculations show an essentially 1D electronic structure with large band dispersion and a small HOMO-LUMO gap. Under high pressures (up to 19 GPa), the conductivity increases by 4 orders of magnitude and the activation energy is decreased from 120 meV to only 13 meV, with an abrupt change observed around 10 GPa, suggesting a structural phase transition under pressure.

Gold(iii) bis(dithiolene) complexes: from molecular conductors to prospective anticancer, antimicrobial and antiplasmodial agents.

The anticancer, antimicrobial and antiplasmodial activities of six gold(iii) bis(dithiolene) complexes were studied. Complexes 1-6 showed relevant anticancer properties against A2780/A2780cisR ovarian cancer cells (IC50 values of 0.08-2 µM), also being able to overcome cisplatin resistance in A2780cisR cells. Complex 1 also exhibited significant antimicrobial activity against Staphylococcus aureus (minimum inhibitory concentration (MIC) values of 12.1 ± 3.9 µg mL-1) and both Candida glabrata and Candida albicans (MICs of 9.7 ± 2.7 and 19.9 ± 2.4 µg mL-1, respectively). In addition, all complexes displayed antiplasmodial activity against the Plasmodium berghei parasite liver stages, even exhibiting better results than the ones obtained using primaquine, an anti-malarial drug. Mechanistic studies support the idea that thioredoxin reductase, but not DNA, is a possible target of these complexes. Complex 1 is stable under biological conditions, which would be important if this compound is ever to be considered as a drug. Overall, the results obtained evidenced the promising biological activity of complex 1, which might have potential as a novel anticancer, antimicrobial and antiplasmodial agent to be used as an alternative to current therapeutics.

Hydrogen bonding interactions in single component molecular conductors based on metal (Ni, Au) bis(dithiolene) complexes.

Introduction of hydrogen bonding (HB) interactions in single component conductors derived from nickel and gold bis(dithiolene) complexes is explored with the 2-alkylthio-1,3-thiazole-4,5-dithiolate (RS-tzdt) with R = CH2CH2OH through the preparation of the neutral [Ni(HOEtS-tzdt)2]0 (closed-shell) and [Au(HOEtS-tzdt)2]˙ (radical) complexes. At variance with many other radical gold dithiolene complexes which have a strong tendency to dimerize in the solid state, [Au(HOEtS-tzdt)2]˙ crystallizes into uniform stacks interconnected by strong O-HN HB involving the nitrogen atom of the thiazole ring. [Au(HOEtS-tzdt)2]˙ is isostructural with its neutral, closed-shell nickel analog [Ni(HOEtS-tzdt)2]0, a rare situation in this metal bis(dithiolene) chemistry. It demonstrates how the strength of the HB directing motif can control the overall structural arrangement to stabilize the same structure despite a different electron count. The nickel complex behaves as a band semiconductor with weak room temperature conductivity (1.6 × 10-5 S cm-1), while the gold complex is described as a Mott insulator with a three orders of magnitude improved conductivity (6 × 10-2 S cm-1).

On the path to gold: Monoanionic Au bisdithiolate complexes with antimicrobial and antitumor activities.

The emergence of resistance to antimicrobial and anticancer drugs poses severe threats to public health worldwide, highlighting the need for more efficient treatments. Here, four monoanionic Au bisdithiolate complexes [Au(mnt)2]- (where mnt = 1,1-dicyanoethylene-2,2-dithiolate)(1), [Au(i-mnt)2]- (where i-mnt = 2,2-dicyanoethylene-1,1-dithiolate)(2), [Au(cdc)2]- (where cdc = cyanodithioimido carbonate)(3), and [Au(qdt)2]- (where qdt = quinoxaline-2,3-dithiolate)(4) were screened for their antimicrobial and antitumor activities. Complexes 3 and 4 showed antibacterial activity against Staphylococcus aureus [minimal inhibitory concentration (MIC) = 15.3 and 14.7 µg/mL, respectively]. Complex 3 also caused significant growth inhibition of Candida glabrata (MIC = 7.0 µg/mL). Concentrations of complexes 1-4 up to 125 µg/mL had no growth inhibition activity against Escherichia coli. The cytotoxic activity of complexes 1-4 was evaluated against the ovarian cancer cells A2780 and A2780cisR, sensitive and resistant to cisplatin, respectively. All compounds showed high cytotoxic activities against both tumoral cell lines, exhibiting IC50 values in the low micromolar range (0.9-5.5 µM) upon 48 h incubation. In contrast to complex 1, the complexes 2-4 induced a dose-dependent formation of reactive oxygen species (ROS), similar to the observed for the reference drugs auranofin and cisplatin. Opposite to 4, complexes 1-3 were able to activate caspase 3/7, suggesting the involvement of apoptosis in the mechanism of cell death. Contrasting with cisplatin, complexes 3, 4 and auranofin did not cause DNA damage. Combined, these data provide evidence that these monoanionic gold bisdithiolates, particularly complex 3, are potential lead compounds to further explore as therapeutic drugs.

Electrochemically driven interfacial halogen bonding on self-assembled monolayers for anion detection.

Electrochemically driven interfacial halogen bonding between redox-active SAMs and halide anions was quantitatively studied for the first time. The halogen bond donor properties were switched on by electrochemically controlling the oxidation state of the adsorbates. Experimental data and simulation show high binding enhancement towards halide anions compared to homogeneous systems.

Atropisomerism in a 10-Membered Ring with Multiple Chirality Axes: (3 Z,9 Z)-1,2,5,8-Dithiadiazecine-6,7(5 H,8 H)-dione Series.

For the first time, chirality in (3 Z,9 Z)-1,2,5,8-dithiadiazecine-6,7(5 H,8 H)-dione series was recognized. Enantiomers of the 4,9-dimethyl-5,8-diphenyl analogue were isolated at room temperature, and their thermal stability was determined. X-ray crystallography confirmed the occurrence of a pair of enantiomers in the crystal. Absolute configurations were assigned by comparing experimental and calculated vibrational/electronic circular dichroism spectra of isolated enantiomers. A distorted tesseract (four-dimensional hypercube) was used to visualize the calculated enantiomerization process, which requires the rotation around four chirality axes. Conformers of higher energy as well as several concurrent pathways of similar energies were revealed.

Stable Metallic State of a Neutral-Radical Single-Component Conductor at Ambient Pressure.

Molecular metals have been essentially obtained with tetrathiafulvalene (TTF)-based precursors, either with multicomponent ionic materials or, in a few instances, with single-component systems. In that respect, gold bis(dithiolene) complexes, in their neutral radical state, provide a prototype platform toward such single-component conductors. Herein we report the first single-component molecular metal under ambient pressure derived from such Au complexes without any TTF backbone. This complex exhibits a conductivity of 750 S·cm-1 at 300 K up to 3800 S·cm-1 at 4 K. First-principles electronic structure calculations show that the striking stability of the metallic state finds its origin in sizable internal electron transfer from the SOMO-1 to the SOMO of the complex as well as in substantial interstack and interlayer interactions.

Neutral, closed-shell nickel bis(2-alkylthio-thiazole-4,5-dithiolate) complexes as single component molecular conductors.

Neutral nickel bis(dithiolene) complexes, because of their closed-shell character, are usually considered as insulating materials, unless they are formed out of highly delocalized tetrathiafulvalenedithiolate ligands. We describe here an original series of S-alkyl substituted neutral bis(thiazole-4,5-dithiolate) nickel complexes formulated as [Ni(RS-tzdt)2] (R = Me, Et), which organize in the solid state into uniform stacks and exhibit semiconducting behavior, with room temperature conductivities comparable to those reported in the prototypical [Ni(dmit)2] and [Ni(Et-thiazdt)2] neutral complexes. These findings provide new perspectives in the current search for single component molecular conductors.

Anderson-Type Polyoxometalates Functionalized by Tetrathiafulvalene Groups: Synthesis, Electrochemical Studies, and NLO Properties.

Three polyoxometalates (POMs) functionalized by tetrathiafulvalene (TTF) molecules have been synthesized by a coupling reaction between the Anderson-type POMs [MnMo6O18{(OCH2)3CNH2}2]3- or [AlMo6O18(OH)3{(OCH2)3CNH2}]3- and the TTF carboxylic acid derivative (MeS)3TTF(S-CH2-CO2H). The monofunctionalized TTF-AlMo6 POM contains one TTF group covalently grafted on an Al Anderson platform. The symmetrical TTF-MnMo6-TTF POM possesses two TTF groups grafted on each side of a Mn Anderson derivative while the asymmetrical TTF-MnMo6-SP POM contains a TTF and a spiropyran groups. These three trianionic species have been characterized by elemental analysis, 1H and 13C NMR, FT-IR spectroscopy, ESI-MS spectrometry, and single-crystal X-ray diffraction (for TTF-MnMo6-TTF). In the solid state, the grafted TTF molecules of TTF-MnMo6-TTF POMs interact via S···S and π···π interactions and form chains. The electrochemical properties of the complexes reflect the contributions of both the inorganic POM and the TTF moieties. Despite adsorption of the oxidized hybrid species on the Pt grid working electrode, UV-vis-NIR spectroelectrochemical investigations evidence peaks characteristic of the oxidation of the TTF units. Finally, hyper-Rayleigh scattering (HRS) measurements show that the three novel TTF derivatives exhibit ß values between 20 and 37 × 10-30 esu. Moreover it is observed that the oxidation of the TTF moieties by Fe3+ ions increases the NLO response. These values are in the order of magnitude of that found for the well-known 4-dimethylamino- N-methyl-4-stilbazolium (DAS+) cation (ß = 60 × 10-30 esu).

Impact of bulky phenylalkyl substituents on the air-stable n-channel transistors of birhodanine analogues.

By introducing bulky 2-phenylethyl groups into sulfur-rich electron acceptors, 5,5'-bithiazolidinylidene-2,2'-dione-4,4'-dithione and 5,5'-bithiazolidinylidene-2,4,2',4'-tetrathione, electron transport with the mobility of 0.27 cm2 V-1 s-1 with ambient and long-term stability is achieved in thin-film transistors. Bulky groups destroy the intermolecular S-S network, but the long-term transistor stability is maintained. Here, benzyl groups realize one-dimensional stacking structures, whereas 2-phenylethyl groups lead to herringbone structures.

Electronic Interplay between TTF and Extended-TCNQ Electrophores along a Ruthenium Bis(acetylide) Linker.

A bis(TTF-butadiynyl) ruthenium D-D'-D complex, with intramolecular electronic interplay between the three electron-donating electrophores, was easily converted through a cycloaddition-retroelectrocyclization with TCNQ into a D-A-D'-A-D pentad complex, which exhibits an intense intramolecular charge transfer together with an electronic interplay between the two acceptors along the conjugated organometallic bridge.

Subtle Steric Differences Impact the Structural and Conducting Properties of Radical Gold Bis(dithiolene) Complexes.

Among single component molecular conductors, neutral radical gold dithiolene complexes [(R-thiazdt)2 Au]. derived from the N-alkyl-1,3-thiazoline-2-thione-4,5-dithiolate (R-thiazdt) ligand provide an extensive series of conducting, non-dimerized, half-filled band systems. Analogues of the known R=isopropyl (iPr) derivative were investigated here with R=NMe2 , cyclopropyl (cPr) and n-propyl (nPr), aiming at rationalizing the different solid state structures adopted by these compounds despite very closely related substituents on the heterocyclic nitrogen atom. An original crisscross organization within dimerized chains is observed with R=NMe2 , differing however from the analogous iPr derivative by a 180° rotation of the heterocyclic nitrogen substituent. On the other hand, the cyclopropyl and n-propyl substituents lead to robust, uniform, non-dimerized chains with a strongly 1 D electronic structure and a formal half-filled electronic structure. The semiconducting behaviour of these two radical complexes is characteristic of a Mott insulator, whose sensitivity to external pressure has been evaluated up to 2.5 GPa.

Single-Component Conductors: A Sturdy Electronic Structure Generated by Bulky Substituents.

While the introduction of large, bulky substituents such as tert-butyl, -SiMe3, or -Si(isopropyl)3 has been used recently to control the solid state structures and charge mobility of organic semiconductors, this crystal engineering strategy is usually avoided in molecular metals where a maximized overlap is sought. In order to investigate such steric effects in single component conductors, the ethyl group of the known [Au(Et-thiazdt)2] radical complex has been replaced by an isopropyl one to give a novel single component molecular conductor denoted [Au(iPr-thiazdt)2] (iPr-thiazdt: N-isopropyl-1,3-thiazoline-2-thione-4,5-dithiolate). It exhibits a very original stacked structure of crisscross molecules interacting laterally to give a truly three-dimensional network. This system is weakly conducting at ambient pressure (5 S·cm(-1)), and both transport and optical measurements evidence a slowly decreasing energy gap under applied pressure with a regime change around 1.5 GPa. In contrast with other conducting systems amenable to a metallic state under physical or chemical pressure, the Mott insulating state is stable here up to 4 GPa, a consequence of its peculiar electronic structure.