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The ability to investigate hypervalent iodine(V) fluorides has been limited primarily by their difficult preparation traditionally using harsh fluorinating reagents such as trifluoromethyl hypofluorite and bromine trifluoride. Here, we report a mild and efficient route using Selectfluor to deliver hypervalent iodine(V) fluorides in good isolated yields (72-90%). Stability studies revealed that bicyclic difluoro(aryl)-λ5-iodane 6 was much more stable in acetonitrile-d 3 than in chloroform-d 1, presumably due to acetonitrile coordinating to the iodine(V) centre and stabilising it via halogen bonding.
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Coordination complexes of lanthanide metals with tris-1-naphthylphosphine oxide (Nap3PO, L) have not been previously reported in the literature. We describe here the formation of lanthanide(III) nitrate complexes Ln(NO3)3L4 (Ln = Eu to Lu) and the structures of [Ln(NO3)3L2]·2L (Ln = Eu, Dy, Ho, Er) and L. The core structure of the complexes is an eight-coordinate [Ln(NO3)3L2] with the third and fourth ligands H-bonded via their oxygen atoms to one of the naphthyl rings. The structures are compared with those of the analogous complexes of triphenylphosphine oxide and show that the Ln-O(P) bond in the Nap3PO complexes is slightly longer than expected on the basis of differences in coordination numbers. The reaction solutions, investigated by 31P and 13C NMR spectroscopy in CD3CN, show that coordination of L occurs across the lanthanide series, even though complexes can only be isolated from Eu onwards. Analysis of the 31P NMR paramagnetic shifts shows that there is a break in the solution structures with a difference between the lighter lanthanides (La-Eu) and heavier metals (Tb-Lu) which implies a minor difference in structures. The isolated complexes are very poorly soluble, but in CDCl3, NMR measurements show dissociation into [Ln(NO3)3L2] and 2L occurs.
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Cobalt(III) compounds with tetradentate ligands have been widely employed to deliver cytotoxic and imaging agents into cells. A large body of work has focused on using cobalt(III)-cyclam scaffolds for this purpose. Here, we investigate the cytotoxic properties of cobalt(III) complexes containing 14-membered macrocycles related to cyclam. A breast cancer stem cell (CSC) in vitro model was used to gauge efficacy. Specifically, [Co(1,4,7,11-tetraazacyclotetradecane)Cl2]+ (1) and [Co(1-oxa-4,8,12-triazacyclotetradecane)Cl2]+ (2) were synthesised and characterised, and their breast CSC activity was determined. The cobalt(III) complexes 1 and 2 displayed micromolar potency towards bulk breast cancer cells and breast CSCs grown in monolayers. Notably, 1 and 2 displayed selective potency towards breast CSCs over bulk breast cancer cells (up to 4.5-fold), which was similar to salinomycin (an established breast CSC-selective agent). The cobalt(III) complexes 1 and 2 were also able to inhibit mammosphere formation at low micromolar doses (with respect to size and number). The mammopshere inhibitory effect of 2 was similar to that of salinomycin. Our studies show that cobalt(III) complexes with 1,4,7,11-tetraazacyclotetradecane and 1-oxa-4,8,12-triazacyclotetradecane macrocycles could be useful starting points for the development of new cobalt-based delivery systems that can transport cytotoxic and imaging agents into breast CSCs.
Assuntos
Antineoplásicos , Cobalto , Células-Tronco Neoplásicas , Humanos , Cobalto/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Sobrevivência Celular/efeitos dos fármacosRESUMO
Pyrroles are important N-heterocycles found in medicines and materials. The formation of pyrroles from widely accessible pyrrolidines is a potentially attractive strategy but is an underdeveloped approach due to the sensitivity of pyrroles to the oxidative conditions required to achieve such a transformation. Herein, we report a catalytic approach that employs commercially available B(C6F5)3 in an operationally simple procedure that allows pyrrolidines to serve as direct synthons for pyrroles. Mechanistic studies have revealed insights into borane-catalyzed dehydrogenative processes.
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An asymmetric bi-nuclear copper(II) complex with both cytotoxic and immunogenic activity towards breast cancer stem cells (CSCs) is reported. The bi-nuclear copper(II) complex comprises of two copper(II) centres bound to flufenamic acid and 3,4,7,8-tetramethyl-1,10-phenanthroline. The bi-nuclear copper(II) complex exhibits sub-micromolar potency towards breast CSCs grown in monolayers and three-dimensional cultures. Remarkably, the bi-nuclear copper(II) complex is up to 25-fold more potent toward breast CSC mammospheres than salinomycin (a gold standard anti-breast CSC agent) and cisplatin (a clinically administered metallodrug). Mechanistic studies showed that the bi-nuclear copper(II) complex readily enters breast CSCs, elevates intracellular reactive oxygen species levels, induces apoptosis, and promotes damage-associated molecular pattern release. The latter triggers phagocytosis of breast CSCs by macrophages. As far as we are aware, this is the first report of a bi-nuclear copper(II) complex to induce engulfment of breast CSCs by immune cells.
Assuntos
Antineoplásicos , Complexos de Coordenação , Ácido Flufenâmico/metabolismo , Cobre/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Células-Tronco NeoplásicasRESUMO
The cytotoxic and immunogenic-activating properties of a cobalt(III)-cyclam complex bearing the non-steroidal anti-inflammatory drug, flufenamic acid is reported within the context of anti-cancer stem cell (CSC) drug discovery. The cobalt(III)-cyclam complex 1 displays sub-micromolar potency towards breast CSCs grown in monolayers, 24-fold and 31-fold greater than salinomycin (an established anti-breast CSC agent) and cisplatin (an anticancer metallopharmaceutical), respectively. Strikingly, the cobalt(III)-cyclam complex 1 is 69-fold and 50-fold more potent than salinomycin and cisplatin towards three-dimensionally cultured breast CSC mammospheres. Mechanistic studies reveal that 1 induces DNA damage, inhibits cyclooxygenase-2 expression, and prompts caspase-dependent apoptosis. Breast CSCs treated with 1 exhibit damage-associated molecular patterns characteristic of immunogenic cell death and are phagocytosed by macrophages. As far as we are aware, 1 is the first cobalt complex of any oxidation state or geometry to display both cytotoxic and immunogenic-activating effects on breast CSCs.
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Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Compostos Heterocíclicos , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Cisplatino/farmacologia , Ácido Flufenâmico/metabolismo , Ácido Flufenâmico/farmacologia , Ácido Flufenâmico/uso terapêutico , Complexos de Coordenação/metabolismo , Cobalto/farmacologia , Cobalto/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico , Células-Tronco NeoplásicasRESUMO
Prevention and control of water pollution for maintaining and restoring the wholesomeness of rivers are unavoidable. The current water quality approach of designated best use has some limitations such as it is non-integrative and inflexible with regard to the consideration of variables and does not provide a separate rating scale for a given designated use. We thus used water quality index approach proposed by the Canadian Council of Ministers of the Environment (CCME WQI) to evaluate and develop a separate rating system for drinking and irrigation purposes of rivers Beas, Satluj and their confluence water of the Indian Punjab using information collected over 4 years (2016 to 2019). River Beas exhibited better water quality compared to river Satluj for irrigation as well as for drinking. The overall drinking water quality index (DWQI) for Beas was marginal (45.5), whereas it was poor for Satluj (37.7) and confluence waters (40.1). The spatial variation in DWQI was greater for Satluj compared to Beas and confluence waters reflecting the effect of dumping of untreated industrial and domestic waste waters. Variables such as Total coliform (T. coli), dissolved oxygen (DO), turbidity and biological oxygen demand (BOD) contributed to the deterioration of DWQI. The irrigation water quality index (IWQI) was good for Beas (86), marginal for Satluj (60.1) and fair for confluence waters (71.2). Faecal coliform (F. coli), Kelly ratio (KR) and %Na contributed to the deterioration of IWQI. Calcium-magnesium-bicarbonate (Ca-Mg-HCO3) was the dominant water type in Beas and confluence waters, whereas for Satluj, in addition to Ca-Mg-HCO3, sodium-potassium-chloride-sulphate and mixed water types were also prevalent. The river waters witnessed salinity hazard but did not pose sodicity hazard except at a few locations of Satluj. The study indicates the need to take location specific measures for improving river water quality for drinking as well as irrigation purposes. The current status of water quality calls for an urgent need to formulate stringent policy regulations to maintain the surface water quality.
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Água Potável , Água Subterrânea , Poluentes Químicos da Água , Qualidade da Água , Rios , Monitoramento Ambiental , Canadá , Poluição da Água/análise , Magnésio , Poluentes Químicos da Água/análiseRESUMO
Cancer stem cells (CSCs) are thought to be partly responsible for metastasis and cancer relapse. Currently, there are no effective therapeutic options that can remove CSCs at clinically safe doses. Here, we report the synthesis, characterisation, and anti-breast CSC properties of a series of copper(I) complexes, comprising of non-steroidal anti-inflammatory drugs (NSAIDs) and triphenylphosphine ligands (1-3). The copper(I) complexes are able to reduce the viability of breast CSCs grown in two- and three-dimensional cultures at micromolar concentrations. The potency of the copper(I) complexes towards breast CSCs was similar to salinomycin (an established anti-breast CSC agent) and cisplatin (a clinically used metallopharmaceutical). Cell-based studies showed that the copper(I) complexes are readily, and similarly, internalised by breast CSCs. The copper(I) complexes significantly increase the intracellular reactive oxygen species (ROS) levels in breast CSCs, and their ROS generation profile with respect to time is dependent on the NSAID component present. The generation of intracellular ROS by the copper(I) complexes could be part of the underlying mechanism by which they evoke breast CSC death. As far as we are aware, this is the first study to explore the anti-breast CSC properties of copper(I) complexes.
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Cobre , Neoplasias , Humanos , Espécies Reativas de Oxigênio , Anti-Inflamatórios não Esteroides/farmacologia , Células-Tronco NeoplásicasRESUMO
Complexes [MCl2 Cp*]2 (M=Ir, Rh), [RuCl2 (p-cymene)]2 and [Ir(C^N)2 Cl]2 (HC^N=a, phenylpyridine ; b, phenylpyrazole,) react with imine ligands derived from ο-aminophenol to yield complexes with an exocyclic C=N bond which has a cis or trans configuration. The trans isomer is favoured except for sterically crowded complexes Cp*M (M=Ir, Rh) when the imine has a mesityl substituent, for which the cis isomer is favoured. The complexes undergo photoisomerisation in visible light but revert back to the original isomer over time or when heated. The rate of the thermal reverse isomerisation depends on the imine substituent and the metal fragment. DFT calculations correctly reproduce the favoured isomer and suggest that the reverse isomerisation occurs by a rehybridisation at the N atom as found in organic imines. In addition, a triplet state, thermally accessible by a Minimum Energy Crossing Point (MECP) provides a low energy pathway for reverse isomerisation in the case of the half-sandwich complexes.
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Copper(II)-terpyridine complexes are endowed with the ability to generate reactive oxygen species (ROS) and induce cancer cell death. Here we report the synthesis, characterisation, and anti-breast cancer stem cell (CSC) properties of a series of copper(II)-terpyridine complexes containing aryl sulfonamide groups (1-5). All of the copper(II)-terpyridine complexes adopt distorted square pyramidal geometries and are suitably stable in biologically relevant solutions (PBS and cell culture media). The p-toluene sulfonamide-bearing copper(II)-terpyridine complex 1 is 6-8-fold more potent towards breast CSCs than salinomycin (an established anti-CSC agent) and cisplatin (a metal-based anticancer drug). The copper(II)-terpyridine complex 1 also reduces the formation, size, and viability of three-dimensionally cultured mammospheres, to a similar or better extent than salinomycin and cisplatin. Mechanistic studies show that 1 successfully enters breast CSCs, generates intracellular ROS at short exposure times, partially induces endoplasmic reticulum stress, and triggers apoptosis. To the best of our knowledge, this is the first study to investigate the anti-breast CSC properties of copper(II)-terpyridine complexes.
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Antineoplásicos , Complexos de Coordenação , Neoplasias , Cisplatino/metabolismo , Cobre/farmacologia , Cobre/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Células-Tronco Neoplásicas , Linhagem Celular Tumoral , Neoplasias/metabolismoRESUMO
Mononuclear copper(II)-phenanthroline complexes have been widely investigated as anticancer agents whereas multinuclear copper(II)-phenanthroline complexes are underexplored. Here the synthesis and characterisation of two new binuclear copper(II)-phenanthroline complexes 1 and 2 is reported, comprising of 2,9-dimethyl-1,10-phenanthroline or 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, terminal chloride ligands, and bridging chloride or hydroxide ligands. The binuclear copper(II) complex containing 2,9-dimethyl-1,10-phenanthroline 1 displays nanomolar toxicity towards bulk breast cancer cells and breast cancer stem cells (CSCs) grown in monolayers, >50-fold greater than cisplatin (an anticancer metallodrug) and salinomycin (a gold-standard anti-CSC agent). Spectacularly, 1 exhibits >100-fold greater potency toward three-dimensionally cultured mammospheres than cisplatin and salinomycin. Mechanistic studies show that 1 evokes breast CSC apoptosis by elevating intracellular reactive oxygen species levels and damaging genomic DNA (possibly by an oxidative mechanism). To the best of our knowledge, this is the first study to probe the anti-breast CSC properties of binuclear copper(II)-phenanthroline complexes.
Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Humanos , Feminino , Cisplatino , Cobre , Fenantrolinas/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cloretos , Ligantes , Antineoplásicos/farmacologia , Células-Tronco NeoplásicasRESUMO
The anti-breast cancer stem cell (CSC) properties of a series of gold(i) complexes comprising various non-steroidal anti-inflammatory drugs (NSAIDs) and triphenylphosphine 1-8 are reported. The most effective gold(i)-NSAID complex 1, containing indomethacin, exhibits greater potency for breast CSCs than bulk breast cancer cells (up to 80-fold). Furthermore, 1 reduces mammosphere viability to a better extent than a panel of clinically used breast cancer drugs and salinomycin, an established anti-breast CSC agent. Mechanistic studies suggest 1-induced breast CSC death results from breast CSC entry, cytoplasm localisation, an increase in intracellular reactive oxygen species levels, cyclooxygenase-2 downregulation and inhibition, and apoptosis. Remarkably, 1 also significantly inhibits tumour growth in a murine metastatic triple-negative breast cancer model. To the best of our knowledge, 1 is the first gold complex of any geometry or oxidation state to demonstrate anti-breast CSC properties.
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Fecal immunochemical testing (FIT) has become the most utilized test for colorectal cancer (CRC) screening. This retrospective quality assurance report analyzed data for 411 patients from one academic center in Central New York who underwent FIT between September 2015 and September 2016. All 67 positive tests and 344 of 952 negative tests were analyzed. Subjects from the FIT-negative "control group" were chosen at random. The mean age was 67 years and the male/female distribution was 391/20, with differences between the FIT-positive and -negative groups. FIT was inappropriately used in 210 (51%) of the 411 patients. The most common reasons for inappropriate FIT use were a documented refusal of colonoscopy (39.60% of inappropriate use), FIT occurring within the recommended surveillance interval from previous colonoscopy (27.98%), and a Charlson Co-Morbidity Index score ≥5 (22.87%). Other reasons were a history of adenoma (9.25%), family history of CRC/high-risk adenoma <60 years of age (5.84%), active/overt gastrointestinal bleed (4.87%), history of CRC (1.46%), and history of inflammatory bowel disease (1.46%). The results of this study show that FIT is being utilized inappropriately about 50% of the time.
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Introduction: In this study, we aimed to identify the differences in sociodemographic variables and reasons for termination of pregnancy (TOP) between married women and single/divorced women. We hope that this study can guide future policies and interventions to reduce the incidence of unsupported pregnancies in this profile group of women. Methods: We retrospectively evaluated the sociodemographic data of 802 women who underwent an abortion for social reasons at our institution in Singapore from January 2016 to September 2018. We compared the sociodemographic variables, reasons for and methods of TOP between married and single/divorced women. Results: We analysed data from 524 married women (65.3%) and 278 single/divorced women (34.7%). Married women were more likely to be of older age (29.5 years vs. 24.5 years, P < 0.001), had more living children and higher educational qualifications. The top two cited reason for abortions among married women were having enough children (42.0%) and the inability to afford another child (18.7%). Multivariate analysis showed that women aged >19 years and having more living children were independently associated with recurrent TOPs. Having a tertiary education was noted to be associated with less recurrent TOPs. Conclusion: The most common reasons married women cited for having TOP include having enough children and the lack of financial capacity to afford another child. Recommendations to support women ought to be personalised and comprehensive in addressing their needs rather than offering a standardised support method. Greater emphasis should be placed on post-TOP family planning counselling to reduce repeated TOP.
Assuntos
Aborto Induzido , Gravidez , Criança , Feminino , Humanos , Estudos Retrospectivos , Singapura/epidemiologia , Hospitais Universitários , EscolaridadeAssuntos
Vacinas contra Influenza , Influenza Humana , Complicações Infecciosas na Gravidez , Coqueluche , Gravidez , Feminino , Humanos , Influenza Humana/prevenção & controle , Estudos Transversais , Coqueluche/prevenção & controle , Vacinação , Vacinas contra Influenza/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , Inquéritos e Questionários , Complicações Infecciosas na Gravidez/prevenção & controle , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
We report the synthesis, characterisation, and anti-osteosarcoma properties of a gallium(III) complex (1) comprising of two 1,10-phenanthroline ligands and salicylate, a non-steroidal anti-inflammatory drug. The gallium(III) complex 1 displays micromolar potency towards bulk osteosarcoma cells and osteosarcoma stem cells (OSCs). Notably, the gallium(III) complex 1 exhibits significantly higher toxicity towards OSCs grown in monolayer and three-dimensional cultures than cisplatin, a frontline anti-osteosarcoma drug. Nuclei isolation and immunoblotting studies show that the gallium(III) complex 1 enters osteosarcoma cell nuclei and induces DNA damage. Flow cytometry and cytotoxicity studies (in the presence of prostaglandin E2) indicate that the gallium(III) complex 1 downregulates cyclooxygenase-2 (COX-2) expression and kills osteosarcoma cells in a COX-2-dependent manner. Further, the mode of osteosarcoma cell death evoked by the gallium(III) complex 1 is characterised as caspase-dependent apoptosis.
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Antineoplásicos , Neoplasias Ósseas , Gálio , Osteossarcoma , Humanos , Fenantrolinas/farmacologia , Gálio/farmacologia , Gálio/uso terapêutico , Salicilatos/farmacologia , Salicilatos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Linhagem Celular Tumoral , Osteossarcoma/tratamento farmacológico , Apoptose , Células-Tronco/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Herein we report the reactivity of the proligand tris(2-pyridylthio)methane (HTptm) with various Alkaline Earth (AE) reagents: (1) dialkylmagnesium reagents and (2) AE bis-amides (AE = Mg-Ba). Heteroleptic complexes of general formulae [Mg(Tptm)(R)] (R = Me, nBu; Tptm = {C(S-C5H4N)3}-) and [AE(Tptm)(N'')] (AE = Mg-Ba; N'' = {N(SiMe3)2}-) were targeted from the reaction of HTptm with R2Mg or [AE(N'')2]2. Reaction of the proligand with dialkylmagnesium reagents led to formation of [{Mg(κ3C,N,N-C{Bu}{S-C5H4N}2)(µ-S-C5H4N)}2] (1) and [{Mg(κ3C,N,N-C{Me}{S-C5H4N}2)(µ-OSiMe3)}2] (2) respectively, as a result of a novel transfer of an alkyl group onto the methanide carbon with concomitant C-S bond cleavage. However, reactivity of bis-amide precursors for Mg and Ca did afford the target species [AE(Tptm)(N'')] (3-AE; AE = Mg-Ca), although these proved susceptible to ligand degradation processes. DFT calculations show that alkyl transfer in the putative [Mg(Tptm)(nBu)] (1m') system and amide transfer in 3-Ca is a facile process that induces C-S bond cleavage in the Tptm ligand. 3-Mg and 3-Ca were also tested as catalysts for the hydrophosphination of selected alkenes and alkynes, including the first example of mono-hydrophosphination of 4-ethynylpyridine which was achieved with high conversions and excellent regio- and stereochemical control.
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Alcenos , Alcinos , Alcenos/química , Amidas , Catálise , LigantesRESUMO
Herein, we report the synthesis of a series of heteroleptic magnesium complexes stabilized with the scorpionate ligand tris(2-pyridylthio)methanide (Tptm). The compounds of the general formula [Mg(Tptm)(X)] (1-X; X = Cl, Br, I) were obtained via protonolysis reaction between the proligand and selected Grignard reagents. Attempts to isolate the potassium derivative K(Tptm) lead to decomposition of Tptm and formation of the alkene (C5H4N-S)2C=C(C5H4N-S)2, and this degradation was also modelled using DFT methods. Compound 1-I was treated with K(CH2Ph), affording the degradation product [Mg(Bptm)2] (2; Bptm = {CH(S-C5NH3)2}-). We analyzed and quantified the steric properties of the Tptm ligand using the structural information of the compounds obtained in this study paired with buried volume calculations, also adding the structural data of HTptm and its CF3-substituted congener (HTptmCF3). These studies highlight the highly flexible nature of this ligand scaffold and its ability to stabilize various coordination motifs and geometries, which is a highly desirable feature in the design of novel organometallic reagents and catalysts.
Assuntos
Magnésio , Cristalografia por Raios X , Ligantes , Modelos MolecularesRESUMO
Copper(II) coordination compounds have been investigated for their anticancer properties for decades, however, none have reached advanced human clinical trials. The poor translation of copper(II) complexes from in vitro studies to (pre)clinical studies can be attributed to their limited efficacy in animal models, which is largely associated with copper leaching and speciation (in biological fluids). Here we report a biologically stable copper(II) complex based on the active site of Type I Cu electron transport proteins. The copper(II) complex 1 comprises of dithiacyclam (with soft and hard donor atoms) and two diclofenac units, a nonsteriodial anti-inflammatory drug (NSAID). Extensive biophysical and electrochemical studies show that the solid state structure of 1 is preserved in solution and that it can access both copper(I) and copper(II) oxidation states without leaching copper or undergoing speciation (in the presence of a cellular reductant). Cell studies show that 1 kills bulk breast cancer cells and highly resistant breast cancer stem cells (CSCs) at micromolar concentrations, and is significantly less toxic towards a panel of non-cancerous cells. Clinically relevant spheroid studies show that 1 is able to inhibit breast CSC-enriched mammosphere formation to a similar extent as salinomycin, a gold standard anti-CSC agent. Mechanistic studies show that 1 evokes breast CSC death by elevating intracellular reactive oxygen species (ROS) and inhibiting cyclooxygenase-2 (COX-2) activity. The former leads to the activation of stress pathways (JNK and p38), which culminates in caspase-dependent apoptosis. This study reinforces the therapeutic potential of copper(II)-NSAID complexes and provides a bioinspired route to develop stable, ROS-generating copper-based anti-CSC drug candidates.
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Antineoplásicos , Complexos de Coordenação , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/química , Linhagem Celular Tumoral , Complexos de Coordenação/química , Cobre/química , Células-Tronco Neoplásicas , Oxirredução , Espécies Reativas de Oxigênio/metabolismoRESUMO
Combined experimental and computational mechanistic studies of the reactions of unsymmetrical, para-substituted N-aryl imidazolium salts, L2-R1,R2, at [MCl2Cp*]2 (M = Rh, Ir) in the presence of NaOAc are reported. These proceed via intermediate N-heterocyclic carbene complexes that then allow an internal competition between two differently substituted aryl rings toward C-H activation to be monitored. At 348 K in dichloroethane C-H activation of the aryl with the more electron-withdrawing substituents is generally favored. DFT calculations show similar barriers for proton transfer and dissociative HOAc/Cl- ligand substitution, with proton transfer favoring electron-donating substituents, and ligand substitution favoring electron-withdrawing substituents. Microkinetic simulations reproduce the experimental preference implying that the ligand substitution step dominates selectivity. For several substrates, notably L2-F,OMe and L2-F,H, running the C-H activation reactions at 298 K in the presence of added [Et4N]Cl reverses the selectivity. The greater availability of chloride in solution makes an alternative dissociative interchange ligand substitution mechanism accessible, leaving proton transfer as selectivity determining and so favoring electron-donating substituents. Our results highlight the potential importance of the ligand substitution step in the interpretation of substituent effects and demonstrate how a simple additive, [Et4N]Cl, can have a dramatic effect on selectivity by changing the mechanism of ligand substitution.