Selective Targeting of Regulated Rhabdomyosarcoma Cells by Trinuclear Ruthenium(II)-Arene Complexes.

The use of benzimidazole-based trinuclear ruthenium(II)-arene complexes (1-3) to selectively target the rare cancer rhabdomyosarcoma is reported. Preliminary cytotoxic evaluations of the ruthenium complexes in an eight-cancer cell line panel revealed enhanced, selective cytotoxicity toward rhabdomyosarcoma cells (RMS). The trinuclear complex 1 was noted to show superior short- and long-term cytotoxicity in RMS cell lines and enhanced selectivity relative to cisplatin. Remarkably, 1 inhibits the migration of metastatic RMS cells and maintains superior activity in a 3D multicellular spheroid model in comparison to that of the clinically used cisplatin. Mechanistic insights reveal that 1 effectively induces genomic DNA damage, initiates autophagy, and prompts the intrinsic and extrinsic apoptotic pathways in RMS cells. To the best of our knowledge, 1 is the first trinuclear ruthenium(II) arene complex to selectively kill RMS cells in 2D and 3D cell cultures.

Trinuclear ruthenium(II) polypyridyl complexes: Evaluation as photosensitizers for enhanced cervical cancer treatment.

Trinuclear ruthenium(II) polypyridyl complexes anchored to benzimidazole-triazine / trisamine scaffolds were investigated as photosensitizers for photodynamic therapy. The trinuclear complexes were noted to produce a significant amount of singlet oxygen in both DMF and aqueous media, are photostable and show appreciable emission quantum yields (ɸem). In our experimental setting, despite the moderate phototoxic activity in the HeLa cervical cancer cell line, the phototoxic indices (PI) of the trinuclear complexes are superior relative to the PIs of a clinically approved photosensitizer, Photofrin®, and the pro-drug 5-aminolevulinic acid (PI: >7 relative to PI: >1 and PI: 4.4 for 5-aminolevulinic acid and Photofrin®, respectively). Furthermore, the ruthenium complexes were noted to show appreciable long-term cytotoxicity upon light irradiation in HeLa cells in a concentration-dependent manner. Consequently, this long-term activity of the ruthenium(II) polypyridyl complexes embodies their ability to reduce the probability of the recurrence of cervical cancer. Taken together, this presents a strong motivation for the development of polymetallic complexes as anticancer agents.

Mononuclear η6-arene ruthenium(II) complexes with pyrazolyl-pyridazine ligands: synthesis, CT-DNA binding, reactivity towards glutathione, and cytotoxicity.

Organometallic η6-arene ruthenium(II) complexes with 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (Ru1, Ru2, and Ru5) and 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (Ru3-4) N,N' heterocyclic and η6-arene (cymene (Ru1-4) or toluene (Ru 5)) have been synthesized. The ruthenium(II) complexes have common "three-legged piano-stool" pseudo-octahedral structures known for half-sandwich complexes. Evolution of their UV-Visible absorption spectra in PBS buffer or DMSO over 24 h confirmed their good solvolysis stability. Titrations of the complexes with the calf thymus DNA (CT-DNA) were monitored using UV-Visible absorption and fluorescence spectroscopies. The complexes interact moderately with CT-DNA and their binding constants are in the order of 104 M-1. Competitive binding of the complexes to a DNA-Hoechst 33,258 depicted competitive displacement of Hoechst from DNA's minor grooves. These complexes bind to glutathione forming GSH-adducts through S coordination by replacement of a halide, with the iodo-analogues having higher binding constants than the chloro-complexes. Cyclic voltammograms of the complexes exhibited one electron-transfer quasi-reversible process. Trends in the molecular docking data of Ru1-5/DNA were similar to those for DNA binding constants. Of the five, only Ru1, Ru3 and Ru5 showed some activity (moderate) against the MCF-7 breast cancer cells with IC50 values in the range of 59.2-39.9 for which Ru5 was the most active. However, the more difficult-to-treat cell line, MDA-MB 231 cell was recalcitrant to the treatment by these complexes.

Evaluating conserved domains and motifs of decapod gonadotropin-releasing hormone G protein-coupled receptor superfamily.

G protein-coupled receptors (GPCRs) are an ancient family of signal transducers that are both abundant and consequential in metazoan endocrinology. The evolutionary history and function of the GPCRs of the decapod superfamilies of gonadotropin-releasing hormone (GnRH) are yet to be fully elucidated. As part of which, the use of traditional phylogenetics and the recycling of a diminutive set of mis-annotated databases has proven insufficient. To address this, we have collated and revised eight existing and three novel GPCR repertoires for GnRH of decapod species. We developed a novel bioinformatic workflow that included clustering analysis to capture likely GnRH receptor-like proteins, followed by phylogenetic analysis of the seven transmembrane-spanning domains. A high degree of conservation of the sequences and topology of the domains and motifs allowed the identification of species-specific variation (up to ~70%, especially in the extracellular loops) that is thought to be influential to ligand-binding and function. Given the key functional role of the DRY motif across GPCRs, the classification of receptors based on the variation of this motif can be universally applied to resolve cryptic GPCR families, as was achieved in this work. Our results contribute to the resolution of the evolutionary history of invertebrate GnRH receptors and inform the design of bioassays in their deorphanization and functional annotation.

Aminoquinoline-based Re(I) tricarbonyl complexes: Insights into their antiproliferative activity and mechanisms of action.

In an effort to develop new potent anticancer agents, two Schiff base rhenium(I) tricarbonyl complexes, containing the ubiquitous aminoquinoline scaffold, were synthesized. Both aminoquinoline ligands and Re(I) complexes showed adequate stability over a 48-h incubation period. Furthermore, the cytotoxic activity of the precursor ligands and rhenium(I) complexes were evaluated against the hormone-dependent MCF-7 and hormone-independent triple negative MDA-MB-231 breast cancer cell lines. Inclusion of the [Re(CO)3Cl]+ entity significantly enhanced the cytotoxicity of the aminoquinoline Schiff base ligands against the tested cancer cell lines. Remarkably, the incorporation of the Schiff-base iminoquinolyl entity notably enhanced the cytotoxic activity of the Re(I) complexes, in comparison with the iminopyridyl entity. Notably, the quinolyl-substituted complex showed up to three-fold higher activity than cisplatin against breast cancer cell lines, underpinning the significance of the quinoline pharmacophore in rational drug design. In addition, the most active Re(I) complex showed better selectivity towards the breast cancer cells over non-tumorigenic FG-0 cells. Western blotting revealed that the complexes increased levels of γH2AX, a key DNA damage response protein. Moreover, apoptosis was confirmed in both cell lines due to the detection of cleaved PARP. The complexes show favourable binding affinities towards both calf thymus DNA (CT-DNA), and bovine serum albumin (BSA), and the order of their interactions align with their cytotoxic effects. The in silico molecular simulations of the complexes were also performed with CT-DNA and BSA targets.

Quinolyl-Based PGM Metallarectangles: Antiproliferative Activity, DNA and BSA Protein Interactions, and a Molecular Docking Perspective.

The increased success of small metal-containing molecules as pharmaceutical agents has prompted investigations into the pharmacological activity of a different class of metal-based compounds; supramolecular coordination complexes (SCCs). Such complexes have been extensively investigated for their anticancer activity, with many displaying activities comparable or superior to available clinical chemotherapeutic drugs. Here, we evaluated a series of quinoline-containing binuclear complexes and metallarectangles for their in vitro anticancer activity in the hormone receptor positive MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. The preliminary cytotoxic screen, in the MCF-7 cell line, revealed that the ligand (7-chloro-4-(pyridin-4-yl)quinoline, L) and metallarectangle [{Ir(µ-Cl)(Cp*)}4 (µ-L)2 ](OTf)4 display superior activity to cisplatin, while [{Ru(p-cymene)}4 (µ-η2 -η2 -C2 O4 )2 (µ-L)2 ](OTf)4 was more potent than cisplatin in the triple-negative MDA-MD-231 cell line. Upon evaluation in a multidose screen, ligand L and metallarectangle [{Ir(µ-Cl)(Cp*)}4 (µ-L)2 ](OTf)4 displayed antiproliferative activity almost two-fold greater than cisplatin in the MCF-7 cell line, while [{Ru(p-cymene)}4 (µ-η2 -η2 -C2 O4 )2 (µ-L)2 ](OTf)4 was over two-times more active than cisplatin in the MDA-MB-231 cell line. Additionally, using the non-tumorigenic MCF-12 A breast epithelial cell line, the compounds demonstrate increased selectivity toward breast cancer cells over non-tumorigenic cells. Furthermore, investigations into the interactions of ligand L and selected complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) indicate favourable binding.

Cytotoxicity Evaluation of Unmodified Paddlewheel Dirhodium(II,II)-Acetate/-Formamidinate Complexes and Their Axially Modified Low-Valent Metallodendrimers.

Two diphenyl formamidine ligands, four dirhodium(II,II) complexes, and three axially modified low-valent dirhodium(II,II) metallodendrimers were synthesized and evaluated as anticancer agents against the A2780, A2780cis, and OVCAR-3 human ovarian cancer cell lines. The dirhodium(II,II) complexes show moderate cytotoxic activity in the tested tumor cell lines, with acetate and methyl-substituted formamidinate compounds displaying increased cytotoxicity that is relative to cisplatin in the A2780cis cisplatin resistant cell line. Additionally, methyl- and fluoro-substituted formamidinate complexes showed comparable and increased cytotoxic activity in the OVCAR-3 cell line when compared to cisplatin. The low-valent metallodendrimers show some activity, but a general decrease in cytotoxicity was observed when compared to the precursor complexes in all but one case, which is where the more active acetate-derived metallodendrimer showed a lower IC50 value in the OVCAR-3 cell line in comparison with the dirhodium(II,II) tetraacetate.

Diversifying academic medicine: One search committee at a time.

Despite increasing attention to lack of diversity among medical education faculty, those traditionally underrepresented in medicine remain so. In 2017, the University of Nevada, Reno School of Medicine approved a new policy to increase diversity in the faculty search process, which includes a mandatory 2-h workshop on best practices in search processes and implicit bias training. Workshop participants were 179 search committee members making up 55 committees from February 2017 to March 2020. Participants completed two separate social validity surveys, one immediately following the workshop and another following the close of their search, and rated various aspects of the workshop. Each search committee completed a Diversity Checklist (DCL) of various mandatory and best practices to be implemented during each search. Historical data on diversity of job applicants, interviewees, and hires over the 5-year period immediately preceding workshop implementation were compared with corresponding diversity data from the participant search committees for a 3-year period following implementation of the workshop. Social validity surveys indicated high ratings pertaining to the benefits of the workshop (means 3.82-4.39 out of 5). Implementation of practices outlined in the DCL were high (94% of mandatory and 87% of best practices). Chi-square analyses of diversity data before and after implementation revealed significant increases in overall diversity (both race and gender) of applicants (p < 0.001), interviewees (p = 0.002), and those offered a position (p = 0.002), in the time period following implementation. Follow-up comparisons found greater increases for gender relative to race/ethnicity.

Rhenium(I) derivatives of aminoquinoline and imidazolopiperidine-based ligands: Synthesis, in vitro and in silico biological evaluation against Plasmodium falciparum.

A small library of aminoquinoline and imidazolopiperidine (IMP)-based ligands, containing the 1,2,3-triazole moiety, and their corresponding tricarbonyl rhenium complexes were synthesised and their inhibitory activities evaluated against the chloroquine-sensitive (CQS) and multidrug-resistant (MDR) strains (NF54 and K1, respectively) of P. falciparum. The quinoline-based compounds (L1, L2, ReL1, and ReL2) were at least six-fold more potent than their IMP-based counterparts (L3, L4, ReL3, and ReL4) against both strains of P. falciparum, with the most promising compound (L1) displaying activity comparable to chloroquine diphosphate (CQDP) in the MDR strain. Additionally, all of the synthesised compounds have resistance indices less than CQDP. To gain insight into a possible mechanism of action, in silico hemozoin docking simulations were performed. These studies proposed that the tested compounds may act via hemozoin inhibition, as the new aminoquinoline-derivatives, with the exception of complex ReL2 (binding affinity: -12.62 kcal/mol), showed higher binding affinities than the reference drug chloroquine (CQ, -13.56 kcal/mol). Furthermore, the ligands exhibited superior binding affinity relative to their corresponding Re(I) complexes, which is reflected in their antiplasmodial activity.

Chemistry of glycol nucleic acid (GNA): Synthesis, photophysical characterization and insight into the biological activity of phenanthrenyl GNA constituents.

The knowledge pertaining to the chemistry and biological activity of glycol nucleic acid (GNA) components, like nucleosides and nucleotides, is still very limited. Herein we report on the preparation of the uracil nucleoside (1) and nucleotide ester GNA (2). The compounds are functionalised with a luminescent phenanthrenyl group. In DMSO, 1 and 2 are brightly fluorescent, with emission maxima at 390 nm, nanosecond decay times (0.6 and 0.75 ns, respectively), and quantum yields of ca. 0.2. In the solid phase, they show excimeric emission, with maxima at 495 nm (1) and 432 nm (2), and decay times of 3.7 ns (1) and 2.9 ns (2). The anticancer activity of the GNA components, as well as gemcitabine hydrochloride, used as a reference drug, were examined in vitro against human cancer HeLa and Ishikawa cells, as well as against normal L929 cells, using a battery of biochemical assays. Furthermore, biodistribution imaging studies were carried out in HeLa cells, with luminescence confocal microscopy, which showed that the compounds localized mainly in the lipophilic cellular compartments. Nucleoside (1) and nucleotide ester (2) features two different anticancer activity profiles. At 24 h of treatment, the nucleoside acts mainly as a toxin and induces necrosis in HeLa cells, whereas the nucleotide ester exhibits pro-apoptotic activity. At longer treatment times (72 h), the nucleoside and the reference, gemcitabine hydrochloride, featured almost identical signs of anticancer activity, such as S-phase cell cycle arrest, proliferation inhibition, and apoptosis induction. In view of this data, one can hypothesize that despite the structural differences, the newly obtained phenanthrenyl GNA nucleoside (1) and gemcitabine may share a common mechanism of anticancer activity in HeLa cancer cells. The GNA components were also examined as antiplasmodial agents against Plasmodium falciparum, in vitro. Nucleoside (1) was found to be more potent than nucleotide (2), displaying activity in the low micromolar range. Furthermore, both phenanthrene derivatives were found to display resistance indices at least 9-fold lower than chloroquine diphosphate (CQDP).

Assessment of medical student burnout: toward an implicit measure to address current issues.

The feasibility of implicitly assessing medical student burnout was explored, using the Implicit Relational Assessment Procedure (IRAP), to measure longitudinal student burnout over the first two years of medical school and directly comparing it with an existing explicit measure of burnout (Maslach Burnout Inventory; MBI). Three successive cohorts of medical students completed both implicit and explicit measures of burnout at several time points during their first two years of medical school. Both assessments were conducted via the internet within a one-week period during the first week of medical school, the end of the first year of medical school, and the end of the second year, though not all cohorts were able to complete the assessments at all time points. Mixed linear models were used to compare the two measures directly, as well as to evaluate changes over time in each measure separately. Minimal correspondence was observed between the implicit and explicit measures of burnout on a within-subject basis. However, when analyzed separately, all subscales of both measures detected significant change over time in the direction of greater levels of burnout, particularly during the first year of medical school. These results provide preliminary evidence the IRAP is able to assess implicit attitudes related to burnout among medical students, though additional research is needed. The IRAP detected consistent improvements in positive implicit attitudes toward medical training during students' second year of medical school, which was not detected by the MBI. Possible implications of these findings are discussed.

Modular synthesis of antimalarial quinoline-based PGM metallarectangles.

A new ditopic, quinoline-based ligand L (7-chloro-4-(pyridin-4-yl)quinoline) was synthesized via a Suzuki cross-coupling reaction. The ligand was utilized to synthesize the corresponding half-sandwich iridium(III) and ruthenium(II) binuclear complexes (1c and 1d) and the subsequent metallarectangles (2c, 2d, 3c, and 3d), via [2 + 2] coordination-driven self-assembly. Single-crystal X-ray diffraction confirmed the proposed molecular structure of the binuclear complex [{IrCl2(Cp*)}2(µ-L)] (1c) and DFT calculations were used to predict the optimized geometry of the rectangular nature of [{Ir(µ-Cl)(Cp*)}4(µ-L)2](CF3SO3)4 (2c). All of the metallarectangles were isolated as their triflate salts and characterized using various spectroscopic (1H, 13C{1H}, DOSY NMR, and IR spectroscopy) and analytical techniques (ESI-MS). The synthesized compounds were screened against the NF54 chloroquine-sensitive (CQS) and K1 chloroquine-resistant (CQR) strains of Plasmodium falciparum. Incorporation of the ubiquitous quinoline core and metal complexation significantly enhanced the in vitro biological activity, with an increase in the nuclearity correlating with an increase in the resultant antiplasmodial activity. This was observed across both parasitic strains, alluding to the potential of supramolecular metallarectangles to act as antiplasmodial agents. Inhibition of haemozoin formation was considered a potential mechanism of action and selected metallarectangles exhibit ß-haematin inhibition activity with near comparable activity to chloroquine.

Subcellular Localisation of a Quinoline-Containing Fluorescent Cyclometallated IrIII Complex in Plasmodium falciparum.

A fluorescent analogue of a previously synthesised N,N-chelated IrIII complex was prepared by coordination of the organic ligand to an extrinsic bis(2-phenylpyridine)iridium(III) fluorophore. This cyclometallated IrIII complex in itself displays good, micromolar activity against the chloroquine-sensitive NF54 strain of Plasmodium falciparum. Live-cell confocal microscopy found negligible localisation of the fluorescent complex within the digestive vacuole of the parasite. This eliminated the haem detoxification pathway as a potential mechanism of action. Similarly, no localisation of the complex within the parasitic nucleus was found, thus suggesting that this complex probably does not interfere with the DNA replication process. A substantial saturation of fluorescence from the complex was found near phospholipid structures such as the plasma and nuclear membranes but not in neutral lipid bodies. This indicates that an association with these membranes, or organelles such as the endoplasmic reticulum or branched mitochondrion, could be essential to the efficacies of these types of antimalarial compounds.

Diversification of quinoline-triazole scaffolds with CORMs: Synthesis, in vitro and in silico biological evaluation against Plasmodium falciparum.

A discrete series of tricarbonyl manganese and rhenium complexes conjugated to a quinoline-triazole hybrid scaffold were synthesised and their inhibitory activities evaluated against Plasmodium falciparum. In general, the complexes show moderate activity with improved inhibitory activities for the photoactivatable manganese(I) tricarbonyl complexes in the malaria parasite. All complexes are active in the dark against the NF54 CQS (chloroquine-sensitive) and K1 MDR (multidrug-resistant) strains of Plasmodium falciparum, with IC50 values in the low micromolar range. Of significance, the complexes retain their activity in the MDR strain with resistance indices ranging between 1.1 and 2.1. The Mn(I) analogues display photodissociation of all three CO ligands upon irradiation at 365 nm. More importantly, the complexes show increased antimalarial activity in vitro upon photoactivation, something not observed by the clinically used reference drug, chloroquine. As a purported mechanism of action, the compounds were evaluated as ß-haematin inhibitors. To further understand the interactions of the complexes, in silico hemozoin docking simulations were performed, attesting to the fact that CO-release could be vital for blocking the hemozoin formation pathway. These results show that this strategy may be a valuable, novel route to design antimalarial agents with higher efficacy.

Recent Advances in the Biological Investigation of Organometallic Platinum-Group Metal (Ir, Ru, Rh, Os, Pd, Pt) Complexes as Antimalarial Agents.

In the face of the recent pandemic and emergence of infectious diseases of viral origin, research on parasitic diseases such as malaria continues to remain critical and innovative methods are required to target the rising widespread resistance that renders conventional therapies unusable. The prolific use of auxiliary metallo-fragments has augmented the search for novel drug regimens in an attempt to combat rising resistance. The development of organometallic compounds (those containing metal-carbon bonds) as antimalarial drugs has been exemplified by the clinical development of ferroquine in the nascent field of Bioorganometallic Chemistry. With their inherent physicochemical properties, organometallic complexes can modulate the discipline of chemical biology by proffering different modes of action and targeting various enzymes. With the beneficiation of platinum group metals (PGMs) in mind, this review aims to describe recent studies on the antimalarial activity of PGM-based organometallic complexes. This review does not provide an exhaustive coverage of the literature but focusses on recent advances of bioorganometallic antimalarial drug leads, including a brief mention of recent trends comprising interactions with biomolecules such as heme and intracellular catalysis. This resource can be used in parallel with complementary reviews on metal-based complexes tested against malaria.

Psychological inflexibility and intolerance of uncertainty moderate the relationship between social isolation and mental health outcomes during COVID-19.

The COVID-19 pandemic has had an enormous impact on human activity worldwide, in part due to many governments issuing stay-at-home orders and limiting the types of social interactions in which citizens can engage. Previous research has shown that social isolation can contribute to psychological distress. The impact of increased social isolation on mental health functioning during the COVID-19 crisis, as well as potential mechanisms to buffer this impact, have yet to be investigated. The current study explored the moderating role of psychological flexibility and related constructs on the relationships between social isolation and mental health outcomes during the COVID-19 pandemic. Cross-sectional data from 278 participants, the majority residing in the United States, were collected during a 3-week period from mid-April to early May 2020 via online survey. A series of hierarchical linear regression analyses indicated statistically significant relationships between social isolation and psychological distress (depression, anxiety, and stress), well-being, and valued living. Psychological inflexibility, intolerance of uncertainty, and emotional suppression significantly moderated these relationships in a number of instances. Greater psychological flexibility and acceptance of difficult experiences appeared to act as a buffer against the negative effects of increased social isolation, while amplifying the benefits of social connectedness. Implications for promoting mental health and buffering against the harmful effects of social isolation during the COVID-19 pandemic and beyond are discussed.

Antimicrobial evaluation of neutral and cationic iridium(III) and rhodium(III) aminoquinoline-benzimidazole hybrid complexes.

A series of neutral and cationic Ir(III) and Rh(III) aminoquinoline-benzimidazole hybrid complexes were synthesised and their inhibitory activities evaluated against Plasmodium falciparum and Mycobacterium tuberculosis. In general, the hybrid complexes display good activity against the chloroquine-sensitive NF54 strain of P. falciparum. The neutral Ir(III)- and Rh(III)-Cp∗ complexes were the most active (IC50 = 0.488 µM for IrIII), maintaining activity against the multidrug-resistant K1 strain. Low to no cytotoxicity against the Chinese hamster ovarian cell line was observed for the tested complexes. Selected active hybrid complexes demonstrated significant inhibition of ß-haematin formation in a cell-free NP-40 assay, suggesting an effect on the host haemoglobin degradation pathway as a potential contributing mechanism of action. When tested against M. tuberculosis H37Rv, most hybrid complexes displayed moderate to good activity. Again, the neutral complexes outperformed the cationic complexes, with the neutral Ir(III)-Cp∗ complexes proving most active (MIC90 = 0.488-1.490 µM).

Bimetallic Paddlewheel-type Dirhodium(II,II) Acetate and Formamidinate Complexes: Synthesis, Structure, Electrochemistry, and Hydroformylation Activity.

Classical hydroformylation catalysts use mononuclear rhodium(I) complexes as precursors; however, very few examples of bimetallic systems have been reported. Herein, we report fully substituted dirhodium(II,II) complexes (C1-C6) containing acetate and diphenylformamidinate bridging ligands (L1-L4). The structure and geometry around these paddlewheel-type, bimetallic cores were confirmed by single-crystal X-ray diffraction. The complexes C3-C6 show electrochemical redox reactions, with the expected reduction (Rh24+/3+) and two oxidation (Rh24+/5+ and Rh25+/6+) electron transfer processes. Furthermore, the bimetallic complexes were evaluated as catalyst precursors for the hydroformylation of 1-octene, with the acetate-containing complexes (C1 and C2) showing near quantitative conversion (>99%) of 1-octene, excellent activity and chemoselectivity toward aldehydes (>98%), with moderate regioselectivity toward linear products. Replacement of the acetate with diphenylformamidinate ligands (complexes C3-C6) yielded moderate-to-good chemoselectivity and regioselectivity, favoring linear aldehydes.

Quinoline-triazole half-sandwich iridium(III) complexes: synthesis, antiplasmodial activity and preliminary transfer hydrogenation studies.

Iridium(iii) half-sandwich complexes containing 7-chloroquinoline-1,2,3-triazole hybrid ligands were synthesised and their inhibitory activities evaluated against the Plasmodium falciparum malaria parasite. Supporting computational analysis revealed that metal coordination to the quinoline nitrogen occurs first, forming a kinetic product that, upon heating over time, forms a more stable cyclometallated thermodynamic product. Single crystal X-ray diffraction confirmed the proposed molecular structures of both isolated kinetic and thermodynamic products. Complexation with iridium significantly enhances the in vitro activity of selected ligands against the chloroquine-sensitive (NF54) Plasmodium falciparum strain, with selected complexes being over one hundred times more active than their respective ligands. No cross-resistance was observed in the chloroquine-resistant (K1) strain. No cytotoxicity was observed for selected complexes tested against the mammalian Chinese Hamster Ovarian (CHO) cell line. In addition, speed-of-action assays and ß-haematin inhibition studies were performed. Through preliminary qualitative and quantitative cell-free experiments, it was found that the two most active neutral, cyclometallated complexes can act as transfer hydrogenation catalysts, by reducing ß-nicotinamide adenine dinucleotide (NAD+) to NADH in the presence of a hydrogen source, sodium formate.

Synthesis and antiproliferative activity of benzimidazole-based, trinuclear neutral cyclometallated and cationic, N

A series of 2-phenyl and 2-pyridyl tris-benzimidazole ligands was reacted with the [Ru(p-cymene)Cl2]2 dimer to yield the corresponding neutral cyclometallated and cationic organoruthenium(ii) complexes. All of the synthesized compounds were characterized using an array of spectroscopic and analytical techniques, including 1H, 13C nuclear magnetic resonance (NMR), infrared spectroscopy and mass spectrometry. The trinuclear compounds were screened for their cytotoxicy against the MCF-7 breast cancer cell line and the triple negative MDA-MB-231 breast cancer cell line at concentrations of 10 and 20 µM. Overall, the 2-pyridyl ligands 10 and 11, and their corresponding trinuclear complexes [16][PF6]3 and [17][PF6]3, show the most promising activity as these compounds significantly reduce the percentage cell survival of MCF-7 and MDA-MB-231 breast cancer cell lines at the aforementioned fixed concentrations. It was observed that 10 and [16][PF6]3 show potency greater than that of cisplatin against the MCF-7 breast cancer cell line, and [17][PF6]3 shows potency comparable to that of cisplatin against the MCF-7 cell line. Additionally, the synthesized compounds were observed to have relatively low cytotoxicty towards MCF-12A breast epithelial cells and relatively higher selectivity towards MCF-7 breast cancer cells compared to cisplatin.