Browsing by Author "Smith, Gregory"

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    Open Access
    Antimalarial Evaluation of Quinoline-triazoleMn(I) and Re(I) PhotoCORMs
    (2019) Ishmail, Fatima-Zahra; Smith, Gregory
    Malaria remains a disease of global health concern, as thousands of people fall victim to it annually. Despite the continuous development of new malaria chemotherapies, the parasite has adapted and mutated, conferring multi-drug resistant strains. The constant emergence of drug-resistant strains of malaria and the decrease in efficacy of most front-line treatments calls for the urgent development of new antimalarial chemotherapeutic drugs. It is of great importance to develop compounds that target resistant strains of malaria. Chloroquine is one of the most significantly studied antimalarials to date and its derivatives have been mainstays in malaria treatment. It has also been established that carbon monoxide (CO) is able to prevent Experimental Cerebral Malaria (ECM) (a severe form of malaria) through the prevention of haemoglobin oxidation.This study investigated the synthesis, characterization and biological evaluation as antiplasmodial agents of two new quinoline-1,2,4-triazole ligands and their respective Mn(I) and Re(I) tricarbonyl complexes. The two ligands differ in the presence of an extended amino-propyl chain conjugated to the quinoline scaffold, which has proven to confer greater antimalarial activity. Furthermore, the complexes were evaluated for their potential as photoCORMs (photo-induced Carbon Monoxide Releasing Molecules) and the CO-releasing effects on the antiplasmodial activity were evaluated. Two manganese tricarbonyl complexes (Mn-1 and Mn-2: contains amino-propyl chain) were evaluated for their CO-releasing properties upon photoexcitation with UV light at 365 nm. Both complexes release CO upon photoexcitation in DCM, DMSO/PBS and DMSO/growth medium solutions. The rate of CO-release is medium-dependent and the Mn-1 complex releases CO faster than the Mn-2 complex. The ligands and metal complexes were evaluated for their in vitro antiplasmodial activity against the NF54-chloroquine-sensitive and the K1-chloroquine-resistant strains of Plasmodium falciparum (P. falciparum). All tested compounds show good antiplasmodial activity with IC50 values in the low micromolar range. The manganese and rhenium analogues exhibit similar antiplasmodial activities, with IC50 values of 3.81 μM and 4.61 μM in the CQ sensitive strain respectively. Both complexes retain their activity in the CQ-resistant strain with resistance indices of 1. The ligand containing the amino-propyl chain (L2) exhibits the greatest antiplasmodial activity with IC50 values of 0.33 μM and 0.69 μM in the CQ-sensitive and -resistant strains respectively. The manganese complex thereof (Mn-2) has IC50 values of 0.54 μM and 1.16 μM in the CQ-sensitive and -resistant strains respectively. The antiplasmodial activity of the manganese complexes Mn-1 and Mn-2 increases 7- and 3- fold respectively upon photoexcitation at 365 nm in the K1-CQ-resistant strain. The increase in antimalarial activity exhibited upon light-induced CO-release presents a promising mechanism of combating drug-resistant P. falciparum. Mechanistic studies of these compounds indicate that they potentially work via β-hematin inhibition, with the metal complexes being greater inhibitors than CQ. Upon photo-induced CO-release, the β-hematin inhibition of complex Mn-1 increases drastically.
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    Open Access
    Dendritic rhodium catalyst precursors for the hydroformylation of olefins
    (2018) Williams, Cody; Smith, Gregory; Mapolie, Selwyn F
    The hydroformylation reaction is the transition-metal catalysed addition of CO/H2 to olefins, resulting in linear and/or branched aldehydes. This reaction is in accordance with Green Chemistry principles, as it operates with 100% atom efficiency and uses renewable feedstocks such as olefins from the Fischer-Tropsch process. Rhodium is the metal of choice when designing catalysts for hydroformylation, owing to its good catalytic activity under mild reaction conditions. The strategy of appending bulky ligands has often been employed to enhance catalytic activity and selectivity. Dendritic wedges are promising to the field of catalysis, as one branch may possess multiple surface terminal groups and the other branch may consist of a mononuclear metal centre. This method differs to classical approaches whereby multinuclear effects are explored to enhance the catalyst activity. The purpose of this study was to synthesize and characterise a series of Fréchet dendrons bearing rhodium Schiff-base moieties at the focal point, and investigate their potential as catalyst precursors in the hydroformylation of olefins. A series of Fréchet dendrons with methyl ester groups at the periphery were prepared. The N,O-salicylaldimine and N,P-iminophosphine Schiff-base ligands were synthesized and consequently coupled to the Fréchet dendrons to yield a new class of Fréchet dendrons with N,O-salicylaldimine or N,P-iminophosphine ligands at the focal point. Complexes of these ligands were synthesized to form a new series of neutral rhodium(I) metallodendrons. Complexation of the N,O-salicylaldimine Fréchet dendrons with the metal-precursor [Rh(μ-Cl)(η 2 :η2 -COD)]2 (where COD = 1,5-cyclooctadiene) afforded the Rh(I)-COD metallodendrons. The Rh(I)-COD metallodendrons were reacted under a carbon monoxide atmosphere to yield a new series of dicarbonyl Rh(I) metallodendrons. The bridge splitting reaction between the N,P-iminophosphine Fréchet dendrons and [Rh(μ-Cl)(CO)2]2 afforded the carbonyl-chloride Rh(I) metallodendrons. The Fréchet dendron ligands and rhodium metallodendrons were fully characterised using an array of spectroscopic (1H, 13C{1H}, 31P{1H} NMR, FT-IR spectroscopy) and analytical (elemental analysis and mass spectrometry) techniques. Single crystal X-ray diffraction confirmed the proposed molecular structure and square-planar geometry around the metal centre for the zeroth generation analogues of the N,O-salicylaldimine and N,P-iminophosphine rhodium metallodendrons. The Rh(I) Schiff-base metallodendrons were applied as catalyst precursors in the hydroformylation of various olefins. All of the catalyst precursors were active in the hydroformylation of 1-octene. The N,O-salicylaldimine metallodendrons displayed good to excellent conversion (78 – 100%), good chemoselectivity (66 – 95%) and moderate regioselectivity (51 – 67%). In contrast, the N,P-iminophosphine metallodendrons displayed low conversion (4 – 8%), good chemoselectivity (76 – 80%) and good regioselectivity (64 – 68%) under the hydroformylation conditions. Notably, the increase in dendron size (G0 – G2) resulted in an increase in the chemoselectivity towards aldehydes. Hydroformylation reactions were conducted using various olefin substrates. These include 1-octene, styrene, 7-tetradecene, methyl oleate, triolein, D-limonene and R-citronellal. The model precursor was active in the hydroformylation of these substrates. More importantly, conversions obtained were promising for styrene (100%), D-limonene (90%), 1-octene (86%), methyl oleate (78%), 7-tetradecene (73%) and triolein (52%). The regioselectivity for the internal olefins ranged between 85 – 98%. These results are particularly promising for tandem-catalytic processes. Mercury drop experiments performed on the zeroth generation analogues of the N,O-salicylaldimine-COD, N,O-salicylaldimine-dicarbonyl and N,P-iminophosphine chloro-carbonyl rhodium(I) metallodendrons displayed suppressed activity in the presence of mercury.
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    Open Access
    Design, synthesis and biological evaluation of bioorganometallic metallarectangles
    (2021) Golding, Taryn; Smith, Gregory
    Malaria is a devastating mosquito-borne disease, characterized by high levels of morbidity and mortality. The absence of a suitable vaccine to offer protection and the emergence of drug-resistant parasite strains continues to be the driving force behind the development of new antimalarial agents. Cancer, which is the second leading cause of deaths globally, accounted for a estimated 9.6 million deaths in 2018. Despite tremendous advances made within the field of drug discovery, the past four decades of cancer chemotherapeutic treatment has largely depended on platinum-based drugs (e.g. cisplatin and its derivatives). Unfortunately, the use of these metallodrugs are accompanied by severe adverse side-effects. Additionally, the evolution of resistant cancer cell sub-types has rendered many of these highly efficacious platinum drugs, ineffective. Utilizing alternative platinum group metals (PGMs), such as iridium and ruthenium, and incorporating known pharmacophoric scaffolds within the framework of a target compound, has been a favourable approach toward combating these obstacles, while further enhancing the pharmacological activity of potential drug candidates. The increased popularity and success of metal-containing compounds 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 PGM SCCs displaying activity greater than or comparable to available clinical chemotherapeutic drugs. Interestingly, however, no studies have investigated the antiplasmodial activity of SCCs, a field that warrants further exploration. Due to the pharmacological activity associated with the quinoline scaffold, this pharmacophore was incorporated into a newly designed N,N'-ditopic ligand (L). The quinoline-containing ligand (L), synthesized via a Suzuki cross-coupling reaction, was reacted with either [Ir(Cp*)(μ-Cl)Cl]2 or [Ru(pcymene)(μ-Cl)Cl]2, via a bridge splitting reaction, to yield the corresponding precursor binuclear complexes. The subsequent iridium(III) and ruthenium(II) metallarectangles were synthesized, as their triflate salts, via coordination-driven self-assembly. All of the compounds were fully characterised using an array of spectroscopic (1H, 13C, DOSY NMR, and FT-IR spectroscopy) and analytical (ESI-MS and melting point analysis) techniques. The known, corresponding 4,4'-bipyridine analogues were also synthesized to evaluate the pharmacological effects of incorporating the quinoline pharmacophore into the framework. Single crystal X-ray diffraction confirmed the proposed molecular structure of the iridium binuclear complex, [{IrCl2(Cp*)}2(μ-L)], and DFT calculations support the proposed structure of metallarectangle [{Ir(μ-Cl)(Cp*)}4(μ-L)2](OTf)4. All of the synthesized compounds were evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive (NF54) and multidrug-resistant (K1) strains of the malaria parasite, Plasmodium falciparum, which is the most virulent species within the genus Plasmodium. In general, incorporation of the quinoline scaffold enhanced the activity at least two-fold, compared to the corresponding 4,4'-bipyridyl analogues. Metal complexation increased the in vitro antiplasmodial activity of the uncoordinated ligands (both L and 4,4'-bipyridine) up to 50-fold, in both the NF54 and K1 strains of the parasite. An increase in the nuclearity of the system resulted in a further increase in activity of up to 12-fold. Furthermore, the resistance indices of the synthesized compounds suggest that they largely retain their activity in the resistant strain of the parasite. Considering that quinoline-containing compounds are generally known to inhibit haemozoin formation, to gain insight into a possible mechanism of action, the quinoline-containing ligand L and selected metallarectangles, [{Ir(Cp*)}4(μ-ƞ 2 -ƞ 2 -C2O4)2(μ-L)2](OTf)4 and [{Ru(p-cymene)}4(μ-ƞ 2 -ƞ 2 - C2O4)2(μ-L)2](OTf)4, were tested for their β-haematin inhibitory activity. Both of the tested metallarectangles displayed promising β-haematin inhibitory activity, with the iridium metallarectangle inhibiting β-haematin formation to almost the same extent as CQ. Furthermore, the new quinoline-containing compounds were evaluated for their in vitro anticancer activity in MCF-7 and MDA-MB-231 breast cancer cell lines. The preliminary cytotoxic screen, in the MCF-7 cell line, revealed that ligand L and metallarectangle [{Ir(μ-Cl)(Cp*)}4(μ-L)2](OTf)4 displayed superior activity to cisplatin. Interestingly, despite being near inactive in the MCF-7 cell line, [{Ru(pcymene)}4(μ-ƞ 2 -ƞ 2 -C2O4)2(μ-L)2](OTf)4 displayed the greatest activity in the triple-negative MDA-MD231 cell line, at 10 μM, exceeding the 45% reduction in cell viability caused by cisplatin at the same concentration. Upon evaluation in a multidose screen, ligand L and metallarectangle [{Ir(μCl)(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-ƞ 2 -ƞ 2 -C2O4)2(μ-L)2](OTf)4 was over two-times more active than cisplatin in the MDA-MB-231 cell line. Finally, the aforementioned compounds were evaluated for their cytotoxicity against the non-tumorigenic MCF-12A cell line. The selectivity indices of these compounds suggest that they demonstrate increased selectivity toward cancerous cells, over healthy cells.
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    Open Access
    Development of aminoquinoline-benzimidazole hybrids and their organometallic complexes as antimicrobial agents against Plasmodium falciparum and Mycobacterium tuberculosis
    (2020) Baartzes, Nadia; Smith, Gregory; Chibale, Kelly
    Malaria and tuberculosis (TB) are infectious microbial diseases contributing to a major global health problem and remain a high priority.The problem is further compounded by the emergence of drug resistant strains of the respective causative agents. New therapies and drug design strategies are thus continually required to overcome this resistance. A unique approach in tackling rising resistance is the use of hybrid chemotherapy, which involves the combination of two or more pharmacophores into a single compound. This study investigated the synthesis, characterisation and pharmacological properties of new organic and ferrocenyl aminoquinoline-benzimidazole hybrid compounds, as well as the corresponding Platinum Group Metal (PGM)-containing complexes. The compounds were screened for their activity against Plasmodium falciparum, and for their cytotoxicity against the Chinese hamster ovarian (CHO) cell-line. In addition, the compounds were also evaluated against Mycobacterium tuberculosis. A series of aminoquinoline-benzimidazole hybrid compounds were prepared. The 2-position of the benzimidazole was substituted with an organic phenyl or pyridyl group, or an organometallic ferrocenyl group. The 5-position of the benzimidazole was varied using substituents with varying hydrophobic and electron-withdrawing or -donating properties, in order to probe the effect on biological activity. These compounds were fully characterised using 1H, 13C{1H}, COSY and HSQC NMR spectroscopy, IR spectroscopy and electrospray ionisation mass spectrometry. The organic and ferrocenyl aminoquinoline-benzimidazole hybrids were screened in vitro against the chloroquine-sensitive (CQS) NF54 strain and multidrug-resistant (MDR) K1 strain of P. falciparum. Most compounds displayed good activity against the sensitive NF54 strain, with IC50 values in the low to sub-micromolar range. With the exception of the pyridyl analogues, most compounds were more potent in the resistant K1 strain. Resistance indices lower than one (RI < 1) were observed in most cases, indicating greater applicability in the resistant strain. The individual aminoquinoline and benzimidazole components were also evaluated in order to determine the value in the use of hybrid agents in comparison to the individual components. In the K1 strain, thehybrid proved more potent than either of the individual components. Using isobologram analysis in the NF54 strain, additive and antagonistic relationships were revealed for the co-administration of the aminoquinoline and benzimidazole components in different relative concentrations. All of the tested hybrids displayed low or no cytotoxicity towards CHO cells and consequent selectivity towards Plasmodium strains. The most active phenyl and ferrocenyl hybrids were subsequently screened for in vivo efficacy against P. bergheiinfected mice. Treatment with the ferrocenyl hybrid resulted in a 92% reduction in parasitemia, proving a more potent inhibitor than the phenyl hybrid (58%). The haem degradation pathway is a known target of many antimalarials, and thus haemozoin inhibition was investigated as a possible mechanism of action of these hybrid compounds. All screened hybrids were found to inhibit synthetic haemozoin (β-haematin) formation in a cell-free assay. A cellular haem fractionation assay was performed on the most active ferrocenyl hybrid, confirming haemozoin inhibition in the parasite. In addition, reactive oxygen species (ROS) generation by this ferrocenyl hybrid was explored using a DNA-cleavage assay, revealing insignificant ROS-generating ability. Furthermore, the aminoquinoline-benzimidazole hybrids were evaluated in vitro against the H37Rv strain of M. tuberculosis. For the phenyl and ferrocenyl hybrids, those with the less hydrophobic 5-position substituents were inactive, while those with the more hydrophobic substituents showed moderate to good activity. Based on logP values, there was a positive correlation between lipophilicity and antimycobacterial activity. In line with this, the more lipophilic ferrocenyl hybrids were consistently more active than their corresponding less lipophilic phenyl analogues. Additionally, in an evaluation of the individual aminoquinoline and benzimidazole components, the hybrid compound was more potent than either component administered individually. The active phenyl hybrid ligands were reacted with [Ir(Cp*)Cl2]2 and [Rh(Cp*)Cl2]2 to yield neutral C^N-coordinated and N-coordinated hybrid complexes. Furthermore, the pyridyl hybrid ligands were reacted with [Ir(Cp*)Cl2]2, [Rh(Cp*)Cl2]2, as well as [Rh(ppy)2Cl]2 to afford cationic N^N-coordinated hybrid complexes. The complexes were fully characterised using the aforementioned spectroscopic and analytical techniques. The C^N- and N^N-coordinated PGM-containing complexes were screened against the NF54 and K1 strains of P. falciparum, generally displaying low to sub-micromolar IC50 values across both strains. In the sensitive NF54 strain, the cationic Rh(III)-ppy complexes were most potent, outperforming the neutral and cationic M-Cp* complexes. The selected complexes (NF54 IC50 ≤ 2 µM) tested in the resistant K1 strain, generally had activity comparable to or lower than that in the NF54 strain (RI ≥ 1). The active hybrid complexes were evaluated against the non-tumorigenic CHO cell-line, displaying low or no cytotoxicity overall. With regards to a possible mechanism of action, the hybrid complexes were found to be potent inhibitors of β-haematin formation. The catalytic ability of selected Ir(III) and Rh(III) C^N-coordinated hybrid complexes, in the transfer hydrogenation of NAD+ to NADH, was also investigated. Using sodium formate as the hydride source, both complexes demonstrated the ability to catalyse the conversion under cell-free assay conditions. However, co-administration of the Ir(III) complex with sodium formate did not have a significant effect on parasite viability. When evaluated against the H37Rv strain of M. tuberculosis, the hybrid complexes generally displayed moderate to good activity. The neutral M-Cp* and cationic Rh(III)-ppy complexes significantly outperformed the cationic M-Cp* complexes. Overall, the neutral Ir(III)-Cp* complexes were most potent, displaying MIC90 values in the low to sub-micromolar range.
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    Open Access
    Dirhodium(II,II) paddlewheel complexes conjugated to a polypyridyl tris-amine scaffold: synthesis and application as asdjncaslpre-catalysts in the hydroformylation of 1-octene
    (2020) de Doncker, Stephen; Smith, Gregory; Ngubane, Siyabonga
    The hydroformylation reaction is the addition of CO/H2 (synthesis gas) to olefins using a transition-metal catalyst to produce linear and/or branched aldehydes. This reaction is in alignment with the Green Chemistry philosophy, applying principles such as using renewable feedstocks, atom economy, and catalysis. The use of rhodium-based catalysts for hydroformylation offers greater selectivity and catalytic activity under milder conditions compared to cobalt-based counterparts. Furthermore, the introduction of sterically demanding ligands such as phosphines are often introduced to enhance selectivity and activity of active catalysts. The conjugation of dendritic structures to transition-metal catalysts, to form metallodendrimers, may be useful in introducing functional groups that alter electronic and steric factors as well as increasing the activity through multinuclearity. Dirhodium(II,II) complexes contain two rhodium atoms, a metal-metal bond and an oxidation state of 4+ over the bimetallic core, resulting in each rhodium atom having an oxidation state of 2+. The electronic and steric influences can be altered by variety of ligands, bearing alkyl or aryl substituents. The purpose of this investigation was to synthesize and characterize a series of dirhodium(II,II) complexes, a suitably functionalized poly-pyridyl scaffold and conjugation of the synthesized complexes to the periphery of the scaffold to form low valent metallodendrimers. A series of diphenylformamidine ligands bearing electron-withdrawing (fluoro) and electrondonating (methyl) substituents at the ortho- and para-postions on the phenyl rings were synthesized. Two dirhodium(II,II) complexes bearing acetate bridging ligands with methyl or trifluoromethyl groups and four dirhodium(II,II) complexes, bearing synthesized diphenylformamidinate bridging ligands, were obtained. A trisamine-based pyridyl scaffold was synthesized and conjugated to each dirhodium complex to afford the corresponding lowvalent metallodendrimers. All ligands, complexes and metallodendrimers were characterized by spectroscopic (1H, 13C{1H}, 19F NMR, FT-IR) and analytical (mass spectrometry) techniques where applicable. The paddlewheel structure of the complex and pseudo-planar nature of the formamidine N-CN system was confirmed by Single crystal X-ray diffraction analyses. The activity of the synthesized complexes and metallodendrimers were evaluated as catalyst precursors in the hydroformylation of 1-octene. Model reactions were carried out with dirhodium(II,II) tetraacetate as a precursor varying time, pressure and temperature resulting in optimized conditions for the formation of aldehydes, with negligible effects on the activity observed in the presence of mercury. Acetate bearing complexes showed near quantitative conversion (>99.8%) of 1-octene, excellent activity and chemoselectivity toward aldehydes (>98%) with moderate regioselectivity towards linear products (40-44%). Excellent conversion (97-99%), moderate to good chemoselectivity toward aldehyde products (59-87%) and moderate to good regioselectivity (48-71%) where obtained for diphenylformamidine compounds. Coordination of the trisamine-based scaffold leads to a general decrease (ca. 10%) in the chemoselectivity toward aldehydes and an anticipated general increase in the regioselectivity towards linear aldehyde of between 3-5% under optimized hydroformylation conditions. Chemoselectivity towards aldehydes was favoured by electron-donating groups over electronwithdrawing groups in the diphenylformamidinate complexes, with regioselectivity favouring linear aldehydes observed for analogous complexes containing electron-withdrawing groups.
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    Expanding the versatility of aminoquinoline organometallic complexes as anticancer and antibacterial agents
    (2023) Zinman, Paige; Smith, Gregory
    Cancer is a devastating non-communicable disease which continues to increase its burden on countries globally. Despite the numerous research and clinical breakthroughs, its prevention is one of the most significant health challenges of the 21st century. Chemotherapy is amongst the most common and effective methods for cancer treatment, however the severe side-effects and acquired chemo-drug resistance by numerous cancers has significantly hindered the efficacy of current chemotherapeutic drugs. Following the limitations of cisplatin and its platinum(II) derivatives, research has focused on the development of chemotherapeutic agents that incorporate alternative platinum-group metals (PGMs). The compelling need for novel treatment modalities has yielded the emergence of photodynamic therapy (PDT) for the treatment of various cancer types, bacterial infections as well as other human ailments. Increasing attention has been given to the development of metal complexes as photosensitisers based on their attractive photophysical and biological properties. The aminoquinoline motif has been recognised as a remarkably versatile pharmacophore owing to its paramount contribution in the clinical success of the historical antimalarial drug, chloroquine. On account of its inherent and ubiquitous biological activity the aminoquinoline structure is represented in numerous clinical drug agents today. This study focused on the synthesis of two series of aminoquinoline-based organometallic complexes comprising of various PGMs (Ir(III), Rh(III) and Ru(II)) as well as the transition metal Re(I). Rhenium is underexplored and highly underestimated for its potentially beneficial application in both therapeutic and diagnostic medical endeavours. With this in mind, the first series consisted of a 4-aminoquinoline-1,3,5-triazine trimeric ligand and the corresponding trihomonuclear Ru(II), Ir(III) and Rh(III) complexes. The second series of 4-aminoquinoline Schiff base ligands, bearing either a pyridyl or quinolyl entity, were subjected to metal complexation yielding mononuclear N,N-chelated Ru(II), Ir(III) and Re(I) organometallic complexes. The synthesized compounds were fully characterised by utilizing assorted spectroscopic (solution-state 1H, 13C{1H}, 2D NMR and solid-state 1H, CP-MAS 13C NMR, FT-IR spectroscopy) and analytical (melting point analysis, mass spectrometry and elemental analysis) techniques. Single crystal X-ray diffraction was also used to validate the proposed molecular structures. Due to the poor solubility in water and most polar solvents coupled with solution instability in coordinating solvents such as DMSO, the trinuclear complexes of Series 1 were not considered for further in vitro biological assessments. However, the compounds of Series 2 were evaluated, in the dark, for in vitro cytotoxicity against the hormone-dependent MCF-7 and hormone-independent triple negative MDA-MB-231 breast cancer cell lines. The results revealed that the Re(I) tricarbonyl complexes show the most promising activity with IC50 values ranging between 8.55 – 6.82 µM. These complexes were up to three times more active than cisplatin in both breast cancer cell lines. The photostable Ru(II) and Ir(III) polypyridyl complexes were investigated for their eligibility as PDT agents. Conducting in vitro cytotoxicity screenings against the 501 melanoma cancer cell line in the dark and in the light, confirmed that all complexes showed enhanced activity upon visible light irradiation at 455 nm. Across all three cancer cell lines the quinolyl-substituted complexes consistently showed superior activity compared to the pyridyl-substituted ones. This observation emphasizes the significance of the quinoline pharmacophore for anticancer drug design. In addition, the minimum inhibitory concentrations (MIC) of the ligands and Re(I) complexes of Series 2 were evaluated against two bacterial strains namely, methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli. All the tested compounds displayed selectivity towards the Gram-positive strain over the Gram-negative bacterial strain. The rhenium tricarbonyl complexes showed enhanced activity compared to the ligands against the MRSA bacterial strain, with the quinolyl-substituted Re(I) analogue displaying the best activity (MIC 12.5 – 25 µM).
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    Iridium (III) photosensitisers for photoredox catalysed carboxylation reactions of ketimines
    (2024) Davids, Tara; Smith, Gregory
    The increasing need for catalytic systems driven by sustainable energy sources continues to motivate the development of processes that utilise photochemical energy to initiate chemical reactions. Photoredox catalysis has piqued great interest in this regard, creating a means for a milder energy source (visible light) to drive chemical reactions and thus revolutionising the field of synthetic radical chemistry and photochemistry. Recently, photoredox catalysis has paved a way for the direct incorporation of CO2 into organic molecules, as a strategy to mitigate CO2 accumulation. Pertinent to this study, is the photoredox catalysed fixation of CO2 to afford unnatural -amino acids, which have important applications in the pharmaceutical industry. Following on from the above, polymetallic transition metal complexes have been promulgated as photocatalysts in processes such as CO2 reduction. These polymetallic photocatalysts were reported to exhibit higher reactivity due to multiple active sites, improved photostability and increased durability in comparison to their mononuclear congeners. We have also demonstrated enhanced photocatalytic abilities of trinuclear heteroleptic ruthenium(II) polypyridyl photocatalysts in the context of the visible light mediated regioselective hydrothiolation reaction of alkenes. The higher yields obtained for the hydrothiolation reaction was attributed to there being a greater driving force for electron transfer processes with the trinuclear complexes. In this study, a series of 2,2'-pyridyl substituted benzimidazole ligands (L1-L3) were synthesised via standard N-alkylation reactions. Subsequently, two mononuclear cationic bis-cyclometalated iridium(III) complexes (C1, C2) and a new trinuclear iridium(III) complex (C3) were synthesised. The complexes (C1-C3) were obtained as racemic mixtures (Λ, Δ isomers) which is an attribute of the helical chirality, inherent to these types of tris-bidentate octahedral complexes. Characterisation of the synthesised ligands and complexes was achieved by 1H NMR, 13C{1H} NMR spectroscopy, infrared spectroscopy and high-resolution mass spectrometry. A crystal structure was also obtained for the new iridium(III) complex (C2), and confirms its molecular structure. 2 Furthermore, the photophysical properties (absorption and emission studies), electrochemical properties, as well as the photostability of the synthesised iridium(III) complexes have been ascertained, where the effects of ligand modifications on these properties have been observed and described. Finally, the catalytic activity of complexes (C1-C3) was evaluated in the visible light mediated photoredox catalysed carboxylation reaction of ketimines using CO2, affording unnatural amino acids. This known reaction was selected as an ideal proof-of-concept reaction, due to the green nature of the reaction (with respect to Green Chemistry principles) and the utility of the -amino acid product. The desired amino acid salt product and/or an additional product was obtained in the photocatalytic reactions with complexes (C1-C3) as the photoredox catalysts. The structure of this additional product was elucidated via spectroscopic analysis. Differences in the photocatalytic activity exhibited by the synthesised iridium complexes (C1-C3) and the model photoredox catalyst, [Ir(ppy)2(dtbbpy)]PF6 is discussed herein. The results obtained from the photocatalysis highlight the importance of judicious ligand design when developing efficient and versatile photosensitisers, and reveal that the benzimidazole scaffold may not be the most well-suited N^N ligand for this application.
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    Structure-activity relationship studies of 2-phenylbenzimidazoles and related organometallic complexes as antiplasmodial agents
    (2018) Rylands, Laa-iqa; Smith, Gregory; Chibale, Kelly
    Malaria remains a huge public health concern, affecting millions of people from all around the world. The widespread resistance by Plasmodium parasites to previously effective quinoline-based drugs and the emerging resistance to current antimalarial therapies, stresses the urgent need for the exploration and development of diverse new classes of compounds. Amongst other requirements, these diverse new compound classes should target resistant strains in particular. In this regard, benzimidazoles have been identified as promising potential drug candidates, displaying potent antiplasmodial activity. Furthermore, benzimidazoles can be chemically transformed into metal-containing organometallic complexes that elevate generally flat benzimidazoles to the third dimension. To date, examples of metal-containing benzimidazoles are extremely limited, with only two reported as having antiplasmodial activity. Thus, we report the syntheses of a series of substituted 2-phenylbenzimidazole ligands, from the cyclo-condensation of o-phenylenediamines and benzaldehyde, as well as the synthesis of Ru(II) and Ir(III) cyclometallated benzimidazole complexes. All of the compounds synthesised were fully characterised by 1H and 13C{1H} Nuclear Magnetic Resonance (NMR) Spectroscopy, Elemental Analysis and Mass Spectrometry. The synthesised 2-phenylbenzimidazoles and metal complexes were screened in vitro against the chloroquine-sensitive NF54 strain and selected complexes were screened against the chloroquine-resistant K1 strain of P. falciparum. In addition, selected compounds were also tested against the Chinese Hamster Ovarian (CHO) mammalian cell-line to evaluate their selectivity. The 2-phenylbenzimidazoles generally displayed weak to moderate antiplasmodial activity against the chloroquine-sensitive NF54 strain, where IC50 values ranged from 3.27 – 32.97 µM. Furthermore, it was demonstrated that the antiplasmodial activities of the 2-phenylbenzimidazoles increased significantly upon metal complexation, using Ru and Ir metals. In general, the antiplasmodial activity of the Ru(II) complexes were significantly better compared to the Ir(III) complexes. The cyclometallated benzimidazole complexes were much more active across both parasite strains (0.12 < IC50 < 4.31), compared to the corresponding ligands tested. The unsubstituted Ru(II) and Ir(III) cyclometallated benzimidazole complexes were found to possess the most potent antiplasmodial activity against the NF54 strain, displaying IC50 values of 0.12 and 0.19 µM, respectively. In most cases, the resistance indices obtained for the select compounds tested were significantly lower compared to chloroquine, which suggested that the compounds are not cross-resistant with chloroquine. Furthermore, cytotoxicity studies indicated that the synthesised compounds had low cytotoxicity and were selective towards the malaria parasites. Additional studies which involved testing the aqueous solubility of selected compounds in PBS buffer at pH 6.5 showed that the introduction of water-solubilising groups improved the compounds solubility significantly. Preliminary mechanistic studies suggested that the synthesised benzimidazoles may have a different mode of action to chloroquine as the compounds did not inhibit β-haematin formation at the maximum concentration of 500 µM.
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    Open Access
    Synthesis and biological evaluation of polynuclear cyclometalated ruthenium, rhodium and iridium complexes based on a PPI dendritic scaffold
    (2013) Sudding, Lara Cathryn; Smith, Gregory
    A series of chelating, bidentate (C,N-) monomeric and dendritic ligands based on a poly(propyleneimine) dendritic scaffold were synthesized via a Schiff-base condensation reaction of the relevant amine and either naphthaldehyde or benzaldehyde. These reactions yielded air- and moisture-stable solids or oils. These compounds were isolated in good yields and characterized using standard spectroscopic and analytical techniques.
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    Synthesis and biological evaluation of trimeric 2,5-disubstituted benzimidazoles and related trinuclear ruthenium(II) organometallic complexes
    (2019) Welsh, Athi; Smith, Gregory; Prince, Sharon
    Cancer remains a global epidemic, with millions affected by the Non-Communicable Disease (NCD) annually. While cisplatin and its platinum(II) derivatives remain widely used chemotherapeutic agents, the undesirable side effects associated with the use of these metallodrugs and the evolution of resistance by cancers limit the scope of use of these platinum(II) complexes. Working towards addressing these issues, research has focused on the development of chemotherapeutic agents based on alternate platinum-group metals (PGMs), with ruthenium metallodrugs being among the most successful in this category. The combination of pharmacophores onto dendritic scaffolds and the combination of these scaffolds with PGMs, yielding multinuclear organometallic complexes is a strategy that has been widely used in rational drug design. However, there is limited research into multinuclear ruthenium compounds, specifically trimetallic ruthenium compounds. With this in mind, the purpose of this study was to synthesize and characterize a series of 2,5-disubstituted benzimidazole-based trimeric compounds and related trinuclear complexes bearing ruthenium(II) metal centers at the periphery. All of the synthesized compounds were screened for their in vitro cytotoxicity against the MCF-7 and MDA-MB-231 breast cancer cell lines and the 501 melanoma cell line. A series of 2,5-disubstituted benzimidazole trimeric ligands were prepared from the cyclocondensation reaction of trimeric o-phenylenediamines with either benzaldehyde or 2-pyridinecarboxaldehyde. Complexation of these 2,5-disubstituted tris-benzimidazole ligands with [RuCl(µ-Cl)(p-cymene)]2 afforded the respective trinuclear neutral CN-chelated and cationic NN-chelated ruthenium(II) complexes. In addition to this, a series of 2-ferrocenyl benzimidazole trimeric compounds were synthesized as non-planar bioisosteres of the 2-aryl 5-substituted benzimidazole trimeric ligands. All of the synthesized compounds were fully characterized using an array of spectroscopic (1H, 13C{1H}, 31P{1H} and 19F{1H} NMR, FT-IR spectroscopy) and analytical (mass spectrometry and elemental analysis) techniques. Preliminary cytotoxic screening of all of the synthesized compounds against the MCF-7 breast adenocarcinoma cell line was done. This preliminary investigation revealed that the 2-pyridyl trimeric ligands and the corresponding trinuclear cationic complexes show superior activity relative to their respective 2-phenyl trimeric ligand counterparts and the corresponding neutral cyclometallated complexes. Consequently, the 2-pyridyl tris-benzimidazole ligands and their corresponding cationic complexes were selected for cytotoxic evaluation against additional cancer cell lines (the MDA-MB-231 breast cancer and the 501mel cancer cell lines). Overall, a 2-pyridyl tris-benzimidazole ligand and two trimetallic cationic complexes showed anticancer activity either comparable or superior to that of cisplatin against the MCF-7 breast cancer cell line (IC50 ≤ 35 µM). Additionally, a 2-pyridyl trimeric benzimidazole ligand and a trimetallic cationic NN-ruthenium(II) complex showed mild activity against the MDA-MB-231 and 501mel cancer cell lines, respectively (IC50 < 35 µM in both cell lines). Selectivity studies based on the non-tumorigenic MCF-12A breast epithelial cell line indicated that selected compounds had low cytotoxicity towards non-tumorigenic cells and showed enhanced selectivity towards the MCF-7 cancerous cells relative to cisplatin. Solvent stability studies of the cationic NN-ruthenium(II) complexes show that these compounds are stable in DMSO for 48 hours under physiological conditions. Additionally, preliminary mechanistic studies of the most active complex indicate that the complex does not interact with guanosine 5’-monophosphate (5’-GMP), suggesting that this complex elicits cytotoxicity via an alternative mechanism of action.
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    The synthesis, characterization and decomposition studies of novel palladacycloalkanes and their precursors
    (2007) Mahamo, Tebello; Moss, John R; Smith, Gregory
    The synthesis and characterization of palladacycloheptane and palladacyclononane complexes based on 1,5-cyclooctadiene (COD), 2,2'bipyridine (bipy), triphenylphosphine (PPh3), and 1,2-bis(diphenylphosphino)ethane (dppe), and their precursors were successfully carried out. The complexes were characterized by 1H, 13C and 31p NMR spectroscopy, mass spectrometry as well as elemental analysis. The palladacycloalkanes were prepared from the bis(alkenyl) complexes of the type cis-[Pd{(CH2)nCH=CH2hL21 (n = 2, 3; L = PPh3; L2 = COD, bipy, dppe) by ring closing metathesis (RCM) reactions followed by hydrogenation.
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    The synthesis, characterization and metathesis reactivity of compounds (with at least one pendant alkene group) of iron, ruthenium and iridium
    (2008) Mbatha, Lancelot Lungelo Mpatho; Moss, John R; Smith, Gregory
    This thesis reports on the synthesis, characterisation and metathesis reactivity studies of (i) ruthenium and iron mono(alkenyl) complexes of the type LM(COh{(CH2)nCH=CH2} (M = iron or ruthenium, L = l1s-C sHs or l1 s-CS(CH3)s and n = 2 - 6), 41 - 51; (ii) iridium complexes of the type Cp*Ir(CI)2{PPh2(CH2)mCH=CH2} (m = 2 - 4 and 6), 69 - 72; and (iii) bis(alkenyl) acyl complexes of the type CpFe(CO){C(O)(CH2)nCH=CH2}{PPh2(CH2)mCH=CH2} (n = 3 - 4, m = 3, 4 and 6), 62 - 65.
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    Synthesis, radiolabelling and pharmacological evaluation of CO-releasing molecules
    (2018) Giffard, Dylan; Smith, Gregory
    The combatting of drug-resistant cancerous cell lines and strains of P. falciparum remain major global health problems to date, with hundreds of thousands of related deaths per annum. Early identification of solid tumours and infections, as well as the discovery of drugs with new mechanisms of action, are paramount in the fight against drug resistance. This study investigates the synthesis, characterisation and biological evaluation of new Mn(I) and Re(I) tricarbonyl metallodendrimers, in addition to the formation of a new 99mTc complex for use in diagnostic imaging. Two series of mono- and multimeric picolylamine ligands based on polyamine scaffolds were prepared. One series of ligands was functionalised with Re(I)- and Mn(I)-tricarbonyl moieties following the [2 + 1] approach, to form a series of cationic complexes. In addition, a second series of neutral bidentate (N,N) Mn(I) complexes were prepared. The ligands and complexes were characterised using a range of spectroscopic and analytical techniques, including 1H, 13C{1H}, and 31P{1H} NMR spectroscopy, infrared spectroscopy, and mass spectrometry. The stability and CO-release properties of the Mn(I) complexes were investigated using UV/Vis absorption spectroscopy. A decrease in the MLCT absorption band suggests the release of CO. CO-release was confirmed using a monomeric Mn(I) complex as a model using the myoglobin assay. The in vitro antiproliferative activity of the Re(I) complexes was investigated against three cancerous cell lines (A431, DLD-1 and A2780) and one non-tumourigenic cell line (BJ). The complexes displayed moderate to good activity, with all IC50 values in the low micromolar range. The tetranuclear complex displayed the highest efficacy against the tested cell lines (IC50 = 6 – 14 µM). Selectivity towards the cancerous cell lines was observed for the tri- and tetranuclear complexes, with higher IC50 values against the BJ cell line. The in vitro antiproliferative activity of the Mn(I) complexes was evaluated against two cancerous cell lines (A431 and A375). The tetranuclear [2 + 1] Mn(I) complex displayed the best activity against both of the tested cell lines. The [2 + 1] complexes displayed higher in vitro activity than their bidentate counterparts. The complexes were evaluated as in vitro antiplasmodial agents against chloroquine-sensitive (NF54) and chloroquine-resistant (K1) strains of P. falciparum. The [2 + 1] Mn(I) complexes displayed enhanced activity over their Re(I) analogues and their bidentate counterparts. The tetranuclear [2 + 1] Mn(I) complex displayed the best activity against the K1 strain (IC50 = 0.99 µM) and the best resistance index (RI = 0.263) of all the tested complexes. Irradiation of selected Mn(I) complexes during incubation with the K1 strain resulted in an almost two-fold increase in activity of the [2 + 1] Mn(I) complexes, but a decrease in activity of the bidentate Mn(I) complexes. Formation of the monomeric radiolabelled product was achieved by reacting 99mTc(bpy)(CO)3 with a monomeric ligand. The product was isolated using preparative HPLC, but the retention time did not match that of the Re(I) analogue, likely due to the difference in counterion. Radiolabelling of the multimeric ligands was unsuccessful.
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    The development of group VIII trinuclear transition metal complexes as chemotherapeutic and photodynamic therapy agents
    (2024) Welsh, Athi; Smith, Gregory; Prince, Sharon
    Cancer is a non-communicable disease that remains one of the leading causes of morbidity and mortality globally. The detrimental effects of cancer are exacerbated by the emergence and development of resistance to current treatment modalities. The development of new treatment modalities, along with novel therapeutic agents, are vital tools in tackling this resistance. Metal-based complexes offer aid in overcoming chemotherapy resistance, as metal complexes may be used in various treatment modalities for cancer and as novel chemotherapeutic drugs. The enhanced biological activity and novel mechanisms of action of trimetallic complexes, as exemplified by BBR3464, lend impetus to the investigation of trinuclear complexes which may lead to the identification of new metallodrug candidates. The purpose of this study was to investigate the synthesis and characterization of a series of trinuclear transition metal- containing complexes based on the benzimidazole scaffold, and the investigation of the applicability of these complexes as different treatment modalities for cancer. A series of trimetallic 2-ferrocenylbenzimidazole complexes, along with their respective mononuclear congeners, were prepared. The 5-position of the benzimidazole scaffold was substituted with varying hydrophobic electron-withdrawing or -donating functionalities, to offer insight into the effect of these substituents on the overall biological activity. However, due to the observed limited aqueous solubility of the trinuclear 2-ferrocenylbenzimidazole complexes, attempts at the improvement of the water solubility of the aforementioned complexes was undertaken. Several strategies were employed, including the use of chemical oxidants and β-cyclodextrin inclusion, with limited success. The preliminary evaluation of the in vitro cytotoxicity of the series of mono- and tri-nuclear 2-ferrocenylbenzimidazole complexes revealed that the trinuclear complexes were initially soluble in biological media. However, the trinuclear complexes gradually precipitated out of biological media within a few hours. On the other hand, the mononuclear complexes showed very mild cytotoxic activity in the MCF-7 breast cancer cell line and no significant activity in the triple-negative MDA-MB-231 breast cancer cell line at the tested concentrations. Additionally, in silico molecular docking studies of all the complexes revealed that the trinuclear 2-ferrocenylbenzimidazole complexes were predicted to bind and interact with oncogenic proteins more favourably relative to their mononuclear congeners. A second series of novel trinuclear benzimidazole-based ruthenium(II) polypyridyl complexes, were synthesized and characterized. The ruthenium(II) polypyridyl complexes were fully characterized using an array of spectroscopic and analytical techniques, including one- and two-dimensional Nuclear Magnetic Resonance (NMR) spectroscopy, Infrared (IR) spectroscopy and high-resolution electrospray ionisation mass spectrometry. These complexes comprised of either the trisamine or the s-triazine core/ central functionality to probe the effects of the aforementioned central moieties on the applicability of the complexes as photosensitizers for photodynamic therapy (PDT). Investigation of the photophysicochemical properties of the ruthenium(II) polypyridyl complexes revealed that the complexes produce a substantial quantity of singlet oxygen in both N,N-dimethylformamide (DMF) and aqueous media. Additionally, the ruthenium(II) complexes were noted to show appreciable photostability and have significant emission quantum yields (ɸem). In the dark, all the ruthenium(II) polypyridyl complexes showed negligible in vitro cytotoxicity in the HeLa cervical cancer cell line at all the tested concentrations (up to 300 µM). However, upon irradiation with blue light (at 455 nm), all the complexes showed appreciable cytotoxicity, with phototoxicity index (P.I.) values greater than some clinically used PDT agents. Furthermore, investigation of the long-term photocytotoxicity of the ruthenium(II) polypyridyl complexes revealed that these complexes show appreciable long-term cytotoxicity upon light irradiation in HeLa cells in a concentration-dependent manner. This highlights the ability of the complexes to reduce the probability of cervical cancer recurrence. Importantly, in both the short-term and long-term cytotoxic evaluations, the trinuclear complexes were noted to show enhanced photocytotoxicity relative to the mononuclear complex. A third, and final, series of benzimidazole-based ruthenium(II) arene complexes were prepared. These ruthenium(II) arene complexes all consisted of the same 2-quinolylbenzimidazole ligand, however, the η6-arene ancillary ligand bound to the ruthenium(II) metal centers was varied. This was to investigate the crucial role of the η6-arene ligand in modulating the overall cytotoxicity of the resultant trinuclear complexes. All the synthesized arene complexes showed appreciable stability in biological media at physiological conditions. Preliminary in vitro cytotoxicity investigations at two fixed concentrations (10 µM and 20 µM) in an eight-cancer cell line panel revealed that the complexes showed enhanced cytotoxicity in the rhabdomyosarcoma (RMS) cell lines. Further biological evaluation at various concentrations resulted in the identification of one lead complex which shows enhanced cytotoxicity and selectivity towards RMS relative to clinically used cisplatin. Additionally, investigation of the long-term cytotoxicity of the lead ruthenium(II) complex brought to light that the complex maintains its superior cytotoxicity and selectivity relative to cisplatin in the long-term (>15 days after treatment). Remarkably, the lead ruthenium(II) complex inhibits the migratory ability of metastatic RMS cells and maintains its enhanced cytotoxicity compared to cisplatin in the 3D multicellular tumour spheroid model. Mechanism of action studies showed that the lead ruthenium(II) complex effectively induces genomic DNA damage, initiates autophagy and up-regulates both the intrinsic and extrinsic apoptotic pathways to elicit cell death in RMS cells.