The Antimicrobial Properties of PdII - and RuII -pyta Complexes.

Infections associated with antimicrobial resistance (AMR) are poised to become the leading cause of death in the next few decades, a scenario that can be ascribed to two phenomena: antibiotic over-prescription and a lack of antibiotic drug development. The crowd-sourced initiative Community for Open Antimicrobial Drug Discovery (CO-ADD) has been testing research compounds contributed by researchers around the world to find new antimicrobials to combat AMR, and during this campaign has found that metallodrugs might be a promising, yet untapped source. To this end, we submitted 18 PdII - and RuII -pyridyl-1,2,3-triazolyl complexes that were developed as catalysts to assess their antimicrobial properties. It was found that the Pd complexes, especially Pd1, possessed potent antifungal activity with MICs between 0.06 and 0.125 µg mL-1 against Candida glabrata. The in-vitro studies were extended to in-vivo studies in Galleria mellonella larvae, where it was established that the compounds were nontoxic. Here, we effectively demonstrate the potential of PdII -pyta complexes as antifungal agents.

A bis(pyridyl)-N-alkylamine/Cu(i) catalyst system for aerobic alcohol oxidation.

Herein a bis(pyridyl)-N-alkylamine/CuI/TEMPO/NMI catalyst system is reported for aerobic oxidation of a variety of primary alcohols to the corresponding aldehydes using readily available reagents, at room temperature and ambient air as the oxidant. ESI-MS analysis of the reaction showed the formation of a [(L1)(NMI)CuII-OOH]+ species, which is a key intermediate in the alcohol oxidation reaction. Evaluation of the effect of reaction parameters on the initial rate of the reaction allowed us to obtain the optimum conditions for catalytic activity. The careful choice of reaction solvent allowed for the oxidation of 4-hydroxybenzyl alcohol, a substrate which proved problematic in previous studies. In the case of 2-pyridinemethanol as substrate, experimental evidence shows that catalytic activity is diminished due to competitive inhibition of the catalyst by the alcohol substrate.

DNA-binding affinity and molecular docking studies of the PEGylated binuclear palladacycle, BTC2, an efficient metallodrug against triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has a low five-year survival rate, especially if the cancer is diagnosed at a late stage and has already metastasized beyond the breast tissue. Current chemotherapeutic options for TNBC rely on traditional platinum-containing drugs like cisplatin, oxaliplatin and carboplatin. Unfortunately, these drugs are indiscriminately toxic, resulting in severe side effects and the development of drug resistance. Palladium compounds have shown to be viable alternatives to platinum complexes since they are less toxic and have displayed selectivity towards the TNBC cell lines. Here we report the design, synthesis, and characterization of a series of binuclear benzylidene palladacycles with varying phosphine bridging ligands. From this series we have identified BTC2 to be more soluble (28.38-56.77 µg/mL) and less toxic than its predecessor, AJ5, while maintaining its anticancer properties (IC50 (MDA-MB-231) = 0.58 ± 0.012 µM). To complement the previous cell death pathway study of BTC2, we investigated the DNA and BSA binding properties of BTC2 through various spectroscopic and electrophoretic techniques, as well as molecular docking studies. We demonstrate that BTC2 displays multimodal DNA binding properties as both a partial intercalator and groove binder, with the latter being the predominant mode of action. BTC2 was also able to quench the fluorescence of BSA, thereby suggesting that the compound could be transported by albumin in mammalian cells. Molecular docking studies revealed that BTC2 is a major groove binder and binds preferentially to subdomain IIB of BSA. This study provides insight into the influence of the ligands on the activity of the binuclear palladacycles and provides much needed information on the mechanisms through which these complexes elicit their potent anticancer activity.

Acid and base strength variations: rationalization for cyclic amine bases and acidic aqua cations.

This perspective highlights and evaluates recent key developments in the thermodynamic approach used to analyze trends in acid and base strength variation. According to this approach, acid and base strength ranking can be interpreted by using thermodynamic or thermochemical cycles. Each cycle generally consists of three independent but well-defined steps. The modus operandi described here entails the identification of the dominant step and the rationalization of its free energy/enthalpy/energy change along a selected series in terms of known structural chemical concepts. Developments in this approach are described by focusing on two related series of bases and two series of acids. In the case of the former the protonation of a series of N-heterocyclic amine bases together with their methyl-substituted analogs receives particular attention while in the case of acids, the acidic properties of aqua dications of elements in period 4 and group 2 are probed. It is illustrated how significant progress in computational chemistry and mass spectrometric techniques can be employed to compare 'inherent' basicity or acidity in the selected families of compounds by using simple gas-phase energy cycles. Unique, dual functions for both electronegativity (element and orbital) and charge density (for aqua cations) indicators are identified and used to evaluate these cycles. Solvent effects (in aqueous solution) are accommodated by including dehydration and hydration changes in appropriately-extended, three-step free energy cycles. It is further suggested that the dominant step in the extended thermodynamic cycle for monomeric aqua cations is the transfer of M(H2O)n2+ complex hydrates from the gas-phase to bulk water. Charge density of the aqua cations again features prominently in proposed rationalizations. Finally, this article also sheds light on salient relationships that exist between empirically and quantum-chemically estimated enthalpy and entropy changes for the aforementioned transfer process.

The palladacycle, BTC2, exhibits anti-breast cancer and breast cancer stem cell activity.

In women globally, breast cancer is responsible for most cancer-related deaths and thus, new effective therapeutic strategies are required to treat this malignancy. Platinum-based compounds like cisplatin are widely used to treat breast cancer, however, they come with limitations such as poor solubility, adverse effects, and drug resistance. To overcome these limitations, complexes containing other platinum group metals such as palladium have been studied and some have already entered clinical trials. Here we investigated the anti-cancer activity of a palladium complex, BTC2, in MCF-7 oestrogen receptor positive (ER+) and MDA-MB-231 triple negative (TN) human breast cancer cells as well as in a human breast cancer xenograft chick embryo model. BTC2 exhibited an average IC50 value of 0.54 µM, a desirable selectivity index of >2, inhibited the migration of ER+ and TN breast cancer cells, and displayed anti-cancer stem cell activity. We demonstrate that BTC2 induced DNA double strand breaks (increased levels of γ-H2AX) and activated the p-ATM/p-CHK2 and p-p38/MAPK pathways resulting in S- and G2/M-phase cell cycle arrests. Importantly, BTC2 sensitised breast cancer cells by triggering the intrinsic (cleaved caspase 9) and extrinsic (cleaved caspase 8) apoptotic as well as necroptotic (p-RIP3 and p-MLKL) cell death pathways and inhibiting autophagy and its pro-survival role. Furthermore, in the xenograft in vivo model, BTC2 displayed limited toxicity and arrested the tumour growth of breast cancer cells over a 9-day period in a manner comparable to that of the positive control drug, paclitaxel. BTC2 thus displayed promising anti-breast cancer activity.

The palladacycle complex AJ-5 induces apoptotic cell death while reducing autophagic flux in rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) forms in skeletal muscle and is the most common soft tissue sarcoma in children and adolescents. Current treatment is associated with debilitating side effects and treatment outcomes for patients with metastatic disease are dismal. Recently, a novel binuclear palladacycle, AJ-5, was shown to exert potent cytotoxicity in melanoma and breast cancer and to present with negligible adverse effects in mice. This study investigates the anti-cancer activity of AJ-5 in alveolar and embryonal RMS. IC50 values of ≤ 0.2 µM were determined for AJ-5 and it displayed a favourable selectivity index of >2. Clonogenic and migration assays showed that AJ-5 inhibited the ability of RMS cells to survive and migrate, respectively. Western blotting revealed that AJ-5 induced levels of key DNA damage response proteins (γH2AX, p-ATM and p-Chk2) and the p38/MAPK stress pathway. This correlated with an upregulation of p21 and a G1 cell cycle arrest. Annexin V-FITC/propidium iodide staining revealed that AJ-5 induced apoptosis and necrosis. Apoptosis was confirmed by the detection of cleaved PARP and increased levels and activity of cleaved caspases-3, -7, -8 and -9. Furthermore, AJ-5 reduced autophagic flux as shown by reduced LC3II accumulation in the presence of bafilomycin A1 and a significant reduction in autophagosome flux J. Finally, pharmacokinetic studies in mice show that AJ-5 has a promising half-life and that its volume of distribution is high, its clearance low and its intraperitoneal absorption is good. Together these findings suggest that AJ-5 may be an effective chemotherapeutic with a desirable mechanism of action for treating drug-resistant and advanced sarcomas.

Phenylacetylene polymerisation mediated by cationic cyclometallated palladium(ii) complexes bearing benzylidene 2,6-diisopropylphenylamine and its derivatives as ligands.

A series of novel cationic palladacycle complexes bearing benzylidene-2,6-diisopropylphenylamine derivatives as ligands and with the general formula [Pd(MeCN)(L)(R-C6H3)CH[double bond, length as m-dash]N{2,6-iPr2-C6H3}][B(3,5-(CF3)2-C6H3)] (R = H, Cl, Br, F, OMe and L = 1,3,5-triaza-7-phosphaadamantane (PTA), tricyclohexylphosphine (PCy3) and triphenylphosphine (PPh3)) were prepared and characterized by a range of analytical techniques. These cationic palladacycle complexes were found to be active precatalysts for the polymerisation of phenylacetylene. The meta-substituent on the cyclometallated ring was found to have a marked effect on the catalyst performance in that complexes, which contained electron-withdrawing substituents, were found to be the most active in the polymerisation process. Furthermore, increasing the steric bulk of the phosphine ligand led to the production of higher molecular weight polyphenylacetylenes (PPA). Polymerisation reactions performed at 25 °C gave a mixture of both cis-transoidal and trans-cisoidal PPA while trans-cisoidal PPA was selectively produced at elevated temperatures (60 °C). Preliminary mechanistic studies demonstrated that polymerisation proceeds via dissociation of the C,N-chelating ligand, and involves the formation of an iminium cationic fragment.

Synthesis and hydroformylation evaluation of Fréchet-type organometallic dendrons with N,O-salicylaldimine Rh(i) complexes at the focal point.

A series of organometallic dendrons containing N,O-salicylaldimine entities at the focal point were synthesised by reacting the N,O-salicylaldimine-functionalised Fréchet dendrons (G0, G1 and G2) with a [Rh(µ-Cl)(η2:η2-COD)]2 dimer to yield the corresponding Rh(COD) [COD = cyclooctadiene] complexes. These Rh(COD) complexes were exposed to an atmosphere of CO to yield a new class of rhodium carbonyl organometallic dendrons with Rh(CO)2 units at the focal point. All the compounds were characterised using standard spectroscopic and analytical techniques, these include nuclear magnetic resonance, infrared spectroscopy, mass spectrometry and single-crystal X-ray diffraction for compounds 1, 4 and 7. All of the complexes were evaluated in the hydroformylation of 1-octene, with excellent conversion and chemoselectivity towards aldehydes. The G0-(CO)2 catalyst precursor (7) was active in the hydroformylation of 1-octene, styrene, 7-tetradecene, methyl oleate, triolein, d-limonene and R-citronellal. The conversion and chemoselectivity towards aldehydes for 7-tetradecene, methyl oleate, triolein and d-limonene were promising. Across a particular dendron series, an increase in chemoselectivity was observed due to the dendritic effect. Mercury drop tests were performed for the G0-analogues and these confirm that the hydroformylation can be attributed to a combination of homogeneous and heterogeneous catalysis.

Recoverable and recyclable water-soluble sulphonated salicylaldimine Rh(I) complexes for 1-octene hydroformylation in aqueous biphasic media.

A series of water-soluble Rh(i) mononuclear complexes of general formula: [Rh(sulphsal-X-R)(COD)] [sulphsal = sulphonated salicylaldimine, COD = cyclooctadiene; where R = H, Cl, CH3 and X = H, (t)Bu] have been synthesized. All the compounds were characterised using various spectroscopic and analytical techniques such as nuclear magnetic resonance spectroscopy, infrared spectroscopy, single crystal X-ray diffraction (for complex ) and mass spectrometry. All the compounds display excellent water-solubility at room temperature and were tested as catalyst precursors in the aqueous biphasic hydroformylation of 1-octene. The catalysts could be easily recovered by phase separation and were used up to 5 times without any significant loss in activity and 1-octene conversion. Very high yields of the expected aldehydes were obtained without addition of any phase transfer agents, co-solvents or hydrophobic ligands. Excellent aldehyde chemoselectivity is observed for all the catalysts but this varied each time the catalysts were recycled, with the formation of a small amount of internal olefins. ICP-OES and mercury poisoning experiments show that a combination of homogeneous catalysis and catalysis mediated by nanoparticles is taking place in these systems.

Cyclometallated platinum(II) complexes of benzylidene-2,6-di-isopropylphenylamine containing bidentate phosphines: synthesis, structural properties and reactivity studies.

The reaction of the cyclometallated complex [PtCl(N^C)(dmso)], 1 (N^C represents the cyclometallated Schiff base, benzylidene-2,6-diisopropylphenylamine), with 1,1'-bis(diphenylphosphino)ferrocene, dppf, bis(diphenylphosphino)methane, dppm, or 1,2-bis(diphenylphosphino)ethane, dppe, in a 2 : 1 ratio or an equimolar ratio using acetone as the solvent produced the corresponding binuclear or mononuclear diphosphine platinum complexes. In the case of the mononuclear complexes, the diphosphines act as either a bidentate ligand or a monodentate ligand depending on the size of the bite angle of the diphosphines, while in the case of the binuclear complexes, the diphosphines act as a bridging ligand between the two metal centres. The solid state structures of some of the binuclear as well as mononuclear species are reported. The mononuclear derivatives were found to show different behaviour in solution and in the solid state when compared to the binuclear analogues. This behaviour is also influenced by the nature of the diphosphine ligands employed.

The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells.

Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti-cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer.

The synthesis and application of novel Ni(II) N-alkyl dipyridylaldiminato complexes as selective ethylene oligomerisation catalysts.

A series of N-alkyl 2,2'-dipyridylamine ligands of general formula (2-C5H3NR)2NR', (a): R = H, R' = Me; (b): R = H, R' = benzyl; (c): R = H, R' = methylcyclohexyl; (d): R = H, R' = neopentyl; (e): R = Me, R' = Me) were prepared by a modified method involving base-mediated N-alkylation with the respective alkyl halide. Reaction of the ligands, a-e, with NiCl2(DME) allowed for the isolation of µ-Cl Ni(ii) complexes: [Ni(µ-Cl){a}Cl]2 (1a); [Ni(µ-Cl){b}Cl]2 (1b); [Ni(µ-Cl){c}Cl]2 (1c); [Ni(µ-Cl){d}Cl]2 (1d) and [Ni(µ-Cl){e}Cl]2 (1e). The complexes were characterised by FT-IR spectroscopy, magnetic susceptibility measurements, mass spectrometry, elemental analyses and in the case of 1a, SCD analysis. In the case of complex 1e, an acid-mediated hydrolysis process was identified. The product of hydrolysis, the protonated ligand and a tetrachloronickelate salt (1e-A), was characterised by SCD analysis. Activation of 1a-1e with alkyl aluminium reagents generated highly active catalysts for the oligomerisation of ethylene, with activities of up to 864 kgoligomers molNi(-1) h(-1) and high selectivity toward the formation of butenes. In general, trans 2-butene was observed as the major isomer, with the exception of 1e. In the case of 1e, the selectivity for 1-butene was 98%, thereby demonstrating the significant effect that the introduction of a low degree of steric pressure in the coordination sphere of the catalyst has on selectivity.

Platinacycloalkane complexes containing [P,N] bidentate ligands: synthesis and decomposition studies.

A new series of platinacyclopentanes (2a-2f) and platinacycloheptanes (3a-3f) of the type [Pt(N^P)(CH2)n] (n = 4, 6) were obtained by the reaction of [Pt(COD)(CH2)n] with the appropriate iminophosphine ligand (1a-1f). These complexes were characterised using a variety of spectroscopic and analytical techniques. X-ray structure analysis of complex 2a revealed a slightly distorted square planar geometry around platinum as a consequence of the ring strain imposed by the [P,N] chelate ring formed and the metallocycloalkane. Thermal decomposition analyses of the platinacycloalkanes revealed that the platinacyclopentanes are markedly stable, with the decomposition reaction requiring temperatures higher than 100 °C to occur. The major products obtained from the thermal decomposition reactions were 1-butene (for platinacyclopentanes) and 1-hexene (for platinacycloheptanes).

A novel binuclear palladacycle complex inhibits melanoma growth in vitro and in vivo through apoptosis and autophagy.

Malignant melanoma is an aggressive skin cancer and it is reported to be the most treatment-resistant human cancer. Here we describe the anti-tumour activity of a novel binuclear palladacycle complex (AJ-5) in vertical growth phase (ME1402) and metastatic (WM1158) melanoma cell lines. We show that compared to normal control cell lines, AJ-5 is more effective in inhibiting the proliferation of ME1402 and WM1158 melanoma cells with IC50 values of 0.19 and 0.20µM, respectively. Flow cytometry analyses showed that AJ-5 induced apoptosis (sub-G1 peak) which was confirmed by Annexin V-FITC/propidium iodide double-staining, nuclear fragmentation and an increase in the levels of PARP cleavage. Furthermore, AJ-5 was shown to induce both intrinsic and extrinsic apoptotic pathways as measured by PUMA, Bax and active caspases. Interestingly, AJ-5 treatment also simultaneously induced the formation of autophagosomes and led to an increase in the autophagy markers LC3II and Beclin1. Inhibition of autophagy reduced AJ-5 cytotoxicity suggesting that AJ-5 induced autophagy was a cell death and not cell survival mechanism. Moreover we show that AJ-5 induces the ATM-CHK2 DNA damage pathway and that its anti-tumour function is mediated by the p38 and ERK1/2 signalling pathways. Importantly, AJ-5 treatment efficiently reduced tumour growth in melanoma bearing mice and induced high levels of autophagy and apoptosis markers. Together these findings suggest that AJ-5 may be an effective chemotherapeutic drug in the treatment of melanoma, a highly aggressive and intractable cancer.

Synthesis, structural characterization and cis-trans isomerization of novel (salicylaldiminato)platinum(II) complexes.

The reaction of cis-[PtCl2(dmso)] with the salicylaldimine ligand, N-(2-hydroxybenzylidene)-2,6-di-isopropylaniline, LA in the presence of sodium acetate in methanol produced both cis- and trans-[PtClLA(dmso)], 1a and 1b. An analogous reaction for the less bulky ligand, N-(2-hydroxybenzylidene)aniline LB produced only cis-[PtClLB(dmso)], 2. The reactions of these dmso complexes with triphenylphosphine also yielded complexes with different geometries depending on the nature of the salicylaldiminato ligand. Thus the cis-trans isomerization of cis-[PtClLA(PPh3)] 3a was investigated both experimentally and computationally, and a tetrahedral transition state was detected in this process. A good agreement of the experimental activation parameters with those determined theoretically using DFT was obtained. LA was also reacted with [PtClMe(cod)] in methanol to yield the corresponding salicylaldiminato complex 6 in which the methyl group is cis to the imine nitrogen. X-ray crystal structures of some compounds obtained are reported.