193 research outputs found
Ruthenium and Other Non-Platinum Anticancer Compounds. In Bioinorganic Medicinal Chemistry
No full textExtraction, characterization and in vitro testing of flavonoids rich fractions obtained from Actinidia macrosperma fruit
No full textIn this PhD study, phenolic compounds extracted from Actinidia macrosperma L. fruit grown in New Zealand, were separated and isolated by series of chromatographic procedures followed by identification on high performance liquid chromatography-tandem mass spectrometry (HPLC-ESI-MS/MS). Single factor experimental design was adopted to optimise the extraction conditions and their phenolic profiles, antioxidant and antihypertensive activities were compared to commercial kiwifruit varieties. Among the extracts tested, 70% aqueous acetone by steeping the A. macrosperma fruit variety showed the highest values of total phenolic (TP) content (823.1±14.4 mg gallic acid equivalent/100 g DW), total flavonoid (TFO) content (170.9±1.9 mg catechin equivalent/100 g DW), total flavanol (TFA) content (82.6±0.6 mg catechin equivalent/100 g DW) and antioxidant capacity (5.1±0.1 mmol Trolox equivalent (TE)/100 g DW and 8.3±0.1 mmol Fe (II) equivalent/100 g DW for DPPH and FRAP assays, respectively). The qualitative and quantitative analysis of each defatted crude extract on high pertformance liquid chromatography-diode array detection (HPLC-DAD) and high pertformance liquid chromatography-tandem mass spectrometry (HPLC-ESI-MS/MS) revealed that 70% aqueous acetone extract from the A. macrosperma fruit contains many potential antioxidant flavonoids compared to commercial kiwifruit varieties namely, Actinidia deliciosa cv Hayward, Actinidia deliciosa cv Sweetgreen, Actinidia chinensis cv Sungold and Actinidia chinensis cv Gold. Quercetin-3-O-galactoside was identified as the most abundant flavonoid among the other flavonoids present in A. macrosperma fruit. Previously undiscovered eleven flavonoids from the A. macrosperma fruit were tentatively identified by using LC-ESI/MS/MS after a series of purification steps including liquid-liquid partitioning, silica gel flash column chromatography, size exclusion chromatography on Sephadex LH-20, and semi-preparative HPLC. It could be concluded that the optimized extraction conditions along with the HPLCESI- MS/MS technique were effectively performed to identify eleven flavonoid compounds, not previously reported from Actinidia macrosperma fruit. This is the first study regarding the phenolic composition and antioxidant properties of new commercial kiwifruit varieties, Actinidia deliciosa cv Sweetgreen, Actinidia chinensis cv Sungold and non-commercial variety, Actinidia macrosperma cultivated in New Zealand. Finally, the effect of Actinidia macrosperma fruit on inhibition of angiotensin converting enzyme (ACE) has not been previously reported and could therefore be recorded as a novel biological activity
A new target for gold(I) compounds:Glutathione-S-transferase inhibition by auranofin
No full text<p>Nowadays, gold compounds occupy a relevant position constituting a promising class of experimental anticancer metallodrugs. Several research efforts have been devoted to the investigations of the pharmacological properties of gold(I) complexes bearing phosphine ligands, such as the antiarthritic drug auranofin, that has also been shown to produce anticancer effects in vitro. In spite of the numerous studies that appeared in the literature the biological mechanisms of action of auranofin and analogues are still controversial. Here, we report on the inhibition effects of glutathione S-transferase P1-1 (GST P1-1) exerted by auranofin. The compound was able to inhibit GST P1-1 with a calculated IC50 of 32.9 +/- 0.5 mu M. Interestingly, the inhibition of GST P1-1 and its cysteine mutants by the gold(I) compound is essentially the same, suggesting that probably the cysteine residues are not so essential for enzyme inactivation in contrast to other reported inhibitors. High-resolution electrospray ionisation Fourier transform ion cyclotron mass spectrometry (ESI FT-ICR MS) studies allowed characterising the binding of the compound with GST enzymes at a molecular level, confirming that similar gold binding sites may be present in the wild-type protein and its Cys mutants. (C) 2012 Published by Elsevier Inc.</p>
A thin-film SnO2 sensor system for simultaneous detection of CO and NO2 with neural signal evaluation
No full textMono- and multidentate anthracenyl-functionalised NHC organometallics: Surprising reactivity and anticancer activity
No full textMetal-based compounds featuring bioactive ligands have been widely used in a variety
of treatments such as chemotherapeutics. One of the notable ligand classes are Nheterocyclic
carbenes (NHCs) which can coordinate to a metal centre forming
anticancer metal–NHC complexes. To track them in cells, metal–NHC complexes can
be functionalised with a fluorescent moiety as an attractive design feature. For this
purpose, pro-carbenes featuring anthracenyl groups were prepared to form metal–
NHC compounds with the methyl-, pyridyl- or triazolyl-functionalised NHC ligand
potentially acting as mono- or bidentate ligands.
An extensive series of MII/III(cym/Cp*)(NHC) complexes (M = Ru, Os, Rh, Ir) was
synthesised and characterised. Some of the reactions of the pro-carbenes with
[Rh(Cp*)Cl2]2 resulted in the formation of unexpected structures. Intramolecular C–C
bond formation between the Cp* and anthracenyl groups with additional auxiliary
interactions between the Rh centre and anthracenyl moieties was observed, which
yielded polydentate ligands, i.e., hepta- and nonadentate ligand systems. The reaction
mechanism involves formation of a tetramethylfulvene complex via deprotonation of a
Cp* methyl group followed by metallocycloaddition and extraction of a chlorido ligand.
Some Rh–C interactions were extremely weak and could be easily displaced by
stronger electron donors such as 1,3,5-triaza-7-phosphaadamantane (pta). The
anticancer activity of the compounds in terms of in vitro cytotoxic activity against
different human cancer cell lines and cell morphology was investigated. The
complexes with monodentate NHC ligands were found to be cytotoxic with 50%
inhibitory concentrations (IC50) values in the low micromolar range, while the
complexes with C,N-chelating ligands and the Rh complexes with its nonadentately
coordinated ligand were found to exhibit greater activity with a slight decrease in the
IC50 values. The anticancer activity studies of the compounds were complemented by
experiments on the interactions of selected complexes with biomolecules amino acids
and DNA to identify biomolecular interaction potential. The reactions with the small
biomolecules proceeded quickly and resulted in the formation of adducts by
undergoing chlorido ligand exchange. A protein crystallographic study on the
interaction with hen egg white lysozyme revealed that the complex bound to L-aspartic
acid along with dissociation of the p-cymene ligand. These properties of the complexes
make them possible candidates for further development of anticancer drugs
Probing the Paradigm of Promiscuity for N‐Heterocyclic Carbene Complexes and their Protein Adduct Formation
No full textMetal complexes can be considered a 'paradigm of promiscuity' when it comes to their reactions with proteins. They often form adducts with a variety of donor atoms in an unselective manner. We have characterized the adducts formed between a series of isostructural N -heterocyclic carbene (NHC) complexes with Ru, Os, Rh, and Ir centers and the model protein hen egg white lysozyme by X-ray crystallography and mass spectrometry. Distinctive behavior for the metal compounds was observed with the more labile Ru and Rh complexes targeting a surface l-histidine moiety through cleavage of p- cymene or NHC co-ligands, respectively. In contrast, the more inert Os and Ir derivatives were detected in an electronegative binding pocket after undergoing ligand exchange of a chlorido ligand for an amino acid side chain. Computational studies supported the binding profiles and hinted at the role of the protein microenvironment for metal complexes eliciting selectivity for specific binding sites on the protein
Reducing childhood illness - fostering growth : an integrated home-based intervention package (IHIP) to improve indoor-air pollution, drinking water quality and child nutrition
No full textChild mortality attributable to pneumonia, diarrhoea and malnutrition accounts globally for the majority of 8.8 million annual deaths. More than half of these deaths are preventable. Available and effective interventions include safe water supply, household water treatment, improved chimney stoves and personal- and home-hygiene and -health messages. In Peru, the current health services reform is focused on shifting responsibilities to peripheral levels; thus, empowering community organisations to manage primary health care services, including health promotion and preventive measures at household level. The current political situation and policy framework to integrate effective preventive interventions that can be delivered at family level, prompted us to test the efficacy of a package of health interventions to reduce childhood illness burden at rural household level.
The goal of this PhD thesis was to assess the efficacy of an Integrated Environmental Home-based-Intervention Package (IHIP), comprised of an improved chimney stoves, access to safe drinking water from solar radiation household water treatment (SODIS), and hygiene education interventions, to reduce morbidity of acute respiratory infections, diarrhoea and poor growth of rural Peruvian children under three years of age. We implemented a community-randomised control field trial (cRCT) in 51 community’s clusters of the San Marcos Province, Cajamarca Region, Peru. The cRCT was divided as follows:
* Set-up, community selection and participatory intervention development: A pilot study was carried out for the selection of the interventions. These were adapted to local customs. The participatory phase is described in detail in Chapters 4 & 5.
* Randomization, enrolment and baseline data collection: Chapter 6 describes the randomisation, enrolment and baseline in detail.
* Carbon monoxide (CO) and Particulate Matter (PM2.5) household air quality assessment: Chapter 7 & 8 describe the efficacy of the OPTIMA-improved stove in improving household air quality in comparison to traditional open fire stoves.
* Morbidity surveillance and field data acquisition: Morbidity data on the daily occurrence of signs and symptoms diarrhoea and respiratory illnesses of children was collected weekly. Anthropometric every two months and microbial data every 6 months. Chapter 9 describes the IHIP impact on morbidity reduction.
* Workshops for a community-driven sustainable dessimination: Chapter 10 describes the community workshops and dissemination processes and dynamics within a socio-ecological framework.
Our community-randomised control trial demonstrated that IHIP reduced 22% per year of child diarrhoea (RR 0.78, 95% CI: 0.49-1.05) and found an odds ratio of 0.71 for diarrhoea prevalence (OR 0.71, 95%, CI: 0.47, 1.06). No effects on the frequency of acute lower respiratory infections (RR 0.99, 95% CI: 0.59, 1.65) or child’s growth rates were found when comparing study arms. We identified three reasons for this moderate diarrhoea reduction: i) hand-washing promotion was universally found in our setting, since it is being promoted by the health care centre; ii) SODIS compliance was moderate: only one third of the beneficiaries were using the method regularly; and iii) the increased awareness for the child’s needs linked to the control intervention, could induce improved child care behaviour. The lack of effect on ALRI, could be linked to insufficient reduction in exposure to household air pollutants and high health service utilisation due to cultural beliefs and health seeking behavoiur. The household air pollution assessment study revealed only moderate reductions of 45% and 27% reduction of PM2.5 and CO, respectively for mothers’ personal exposure. This result was achieved in the best working stoves only. This may most likely not be sufficient to reduce impact on physician-diagnosed pneumonia.
Community participatory meetings and surveys revealed that people’s decisions on adopting household-level environmental and hygiene interventions, was not only based on individual perceptions of their potential gains, but also depended on peer pressure and social network relations. Individual perceptions regarding pollution levels of water and household air (transparent, odourless water vs dirty air environments) influenced perceived gains and the adoption of certain interventions. Access to information and encouragement from health-care providers and programme implementers also increased adoption.
The IHIP had several additional benefits beyond health outcomes. Mother’s expressed that the stoves could reduce cooking time and wood consumption, which translated into cost saving. They also could perform other task while cooking. Regarding the kitchen sink, the mothers expressed it facilitated handwashing, and washing of utensils with detergent, generating a cleaner kitchen environment that fostered home and food hygiene. We believe that the IHIP package motivated families to improve the kitchen living area in general. The high acceptance and sustained use was not only observed in the IHIP families but also in non-participating families that had copied the OPTIMA-improved stove after the community engagement in the desimination activities. We can also conclude that the IHIP package added to the family status, improved quality of life and impacted on their livelihoods, by empowering the beneficiary families.
In conclusion, through this project we envisaged to demonstrate how an integrated package could be implemented at the household level in rural areas of Peru and its effect on health, quality of life and livelihoods. However, behaviour change for keeping maintanence of the interventions and use is necessary to achieve compliance, replication and sustainability
Exploiting Tumour Hypoxia to Deliver Mononuclear Bioreductive Cobalt-based Anticancer Chemotherapeutic Agents with Novel Coordination Geometry
No full textTo circumvent the wide range of adverse effects of many traditional anticancer chemotherapeutics, there has been a shift towards targeting methodologies which exploit tumour microenvironmental differences between cancer and healthy cells. One biologically relevant tumour-specific microenvironmental difference is the presence of hypoxic pockets which results in a change in protein expression, cellular energetics, and an overall reducing environment. The reduction potential in these areas is significantly lower than in healthy cells enabling the selective activation-by-reduction of organic and metal-based compounds. CoIII compounds have been identified as potential agents to deliver cytotoxic ligands to tumours due to the significantly faster aqua ligand exchange kinetics for the CoII ion compared to CoIII upon reduction. The electro- and physicochemical properties of the CoIII species can be controlled by the specific ancillary and cytotoxic ligands coordinated to the Co centre.
CoIII compounds containing tetraazamacrocycle ancillary ligands, cyclen and cyclam, were synthesised containing three classes of cytotoxic ligands coordinating through different coordination motifs, namely the O,O’-coordinating hydroxamate (e.g. vorinostat), the O,O’- and S,O-coordinating (thio)maltolate, and S,N-coordinating pyridinecarbothioimide ligands. As the cytotoxic and ancillary ligands have a distinct impact on the overall properties of the final CoIII compound, clear patterns of reduction potential, reversibility, and ligand release. All the Co(cyclen) compounds with O,O’-coordinating ligands were irreversibly reduced while the Co(cyclam) O,O’- and all S,O-derivatives were quasireversible. For these compounds only a portion of the ligands were released by reduction with sodium dithionite. However, for the S,N-coordinating PCA compounds, only the para-fluoro derivative was quasireversible with all other species being irreversibly reduced and complete ligand release observed in 1H NMR spectra.
In normoxic conditions, the bioactivity of the cytotoxic ligand is masked by coordination to CoIII and is an important metric for determining hypoxia-dependent antiproliferative activity. Antiproliferative assays revealed a range of anticancer activities for the ligands with selected compounds showing high potency, especially for vorinostat and those featuring thiomaltol-derived ligands. In virtually all cases, coordination to CoIII resulted in reduced antiproliferative activity demonstrating the potential to improve the selectivity of the native ligands by CoIII coordination. Unfortunately, no significant improvement in antiproliferative activity was observed in vitro when cells were treated with selected CoIII compounds in hypoxic conditions either due to poor reduction of the CoIII centre or poor uptake into the tumour cells. Nevertheless, when the impacts of CoIII–vorinostat species were determined after incubation with AGS cells in vitro under hypoxic conditions, the same spectrum of changes to gene expression and histone acetylation as native vorinostat were observed, thereby demonstrating a degree of intracellular uptake, reduction of CoIII, and ligand release. Despite the lack of hypoxia-dependent antiproliferative activity, this work lays the foundation to further investigate the coordination of cytotoxic ligands with alternative coordination motifs to CoIII centres
Probing the Paradigm of Promiscuity for N-Heterocyclic Carbene Complexes and their Protein Adduct Formation
No full textMetal complexes can be considered a "paradigm of promiscuity" when it comes to their interactions with proteins. They often form adducts with a variety of donor atoms in an unselective manner. We have characterized the adducts formed between a series of isostructural N-heterocyclic carbene (NHC) complexes with Ru, Os, Rh, and Ir centers and the model protein hen egg white lysozyme by X-ray crystallography and mass spectrometry. Distinctive behavior for the metal compounds was observed with the more labile Ru and Rh complexes targeting mainly a surface l-histidine moiety through cleavage of p-cymene or NHC co-ligands, respectively. In contrast, the more inert Os and Ir derivatives were detected abundantly in an electronegative binding pocket after undergoing ligand exchange of a chlorido ligand for an amino acid side chain. Computational studies supported the binding profiles and hinted at the role of the protein microenvironment for metal complexes eliciting selectivity for specific binding sites on the protein
Impact of home environment interventions on the risk of influenza-associated ARI in Andean children : observations from a prospective household-based cohort study
No full textThe Respiratory Infections in Andean Peruvian Children (RESPIRA-PERU) study enrolled children who participated in a community-cluster randomized trial of improved stoves, solar water disinfection, and kitchen sinks (IHIP trial) and children from additional Andean households. We quantified the burden of influenza-associated acute respiratory illness (ARI) in this household-based cohort.; From May 2009 to September 2011, we conducted active weekly ARI surveillance in 892 children age >3 years, of whom 272 (30.5%) had participated in the IHIP trial. We collected nasal swabs during ARI, tested for influenza and other respiratory viruses by RT-PCR, and determined influenza incidence and risk factors using mixed-effects regression models.; The overall incidence of influenza-associated ARI was 36.6/100 child-years; incidence of influenza A, B, and C was 20.5, 8.7, and 5.2/100 child-years, respectively. Influenza C was associated with fewer days of subjective fever (median 1 vs. 2) and malaise (median 0 vs. 2) compared to influenza A. Non-influenza ARI also resulted in fewer days of fever and malaise, and fewer healthcare visits than influenza A-associated ARI. Influenza incidence varied by calendar year (80% occurred in the 2010 season) and IHIP trial participation. Among households that participated in the IHIP trial, influenza-associated ARI incidence was significantly lower in intervention than in control households (RR 0.40, 95% CI: 0.20-0.82).; Influenza burden is high among Andean children. ARI associated with influenza A and B had longer symptom duration and higher healthcare utilization than influenza C-associated ARI or non-influenza ARI. Environmental community interventions may reduce influenza morbidity
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