Conformational analysis of the natural iron chelator myo-inositol 1,2,3-trisphosphate using a pyrene-based fluorescent mimic

myo-Inositol phosphates possessing the 1,2,3-trisphosphate motif share the remarkable ability to completely inhibit iron-catalysed hydroxyl radical formation. The simplest derivative, myo-inositol 1,2,3-trisphosphate [Ins(1,2,3)P3], has been proposed as an intracellular iron chelator involved in iron transport. The binding conformation of Ins(1,2,3)P3 is considered to be important to complex Fe3+ in a 'safe' manner. Here, a pyrene-based fluorescent probe, 4,6-bispyrenoyl-myo-inositol 1,2,3,5-tetrakisphosphate [4,6-bispyrenoyl Ins(1,2,3,5)P4], has been synthesised and used to monitor the conformation of the 1,2,3-trisphosphate motif using excimer fluorescence emission. Ring-flip of the cyclohexane chair to the penta-axial conformation occurs upon association with Fe3+, evident from excimer fluorescence induced by π-π stacking of the pyrene reporter groups, accompanied by excimer formation by excitation at 351 nm. This effect is unique amongst biologically relevant metal cations, except for Ca 2+ cations exceeding a 1:1 molar ratio. In addition, the thermodynamic constants for the interaction of the fluorescent probe with Fe3+ have been determined. The complexes formed between Fe 3+ and 4,6-bispyrenoyl Ins(1,2,3,5)P4 display similar stability to those formed with Ins(1,2,3)P3, indicating that the fluorescent probe acts as a good model for the 1,2,3-trisphosphate motif. This is further supported by the antioxidant properties of 4,6-bispyrenoyl Ins(1,2,3,5)P4, which closely resemble those obtained for Ins(1,2,3)P3. The data presented confirms that Fe3+ binds tightly to the unstable penta-axial conformation of myo-inositol phosphates possessing the 1,2,3-trisphosphate motif. © 2010 The Royal Society of Chemistry.

Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates

As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.

Natural products from Brazilian biodiversity as a source of new models for medicinal chemistry

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Action Of Essential Oils From Brazilian Native And Exotic Medicinal Species On Oral Biofilms.

Essential oils (EO) obtained from twenty medicinal and aromatic plants were evaluated for their antimicrobial activity against the oral pathogens Candida albicans, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus sanguis and Streptococcus mitis. The antimicrobial activity of the EO was evaluates by microdilution method determining Minimal Inhibitory Concentration. Chemical analysis of the oils compounds was performed by Gas chromatography-mass spectrometry (CG-MS). The most active EO were also investigated as to their actions on the biolfilm formation. The most of the essential oils (EO) presented moderate to strong antimicrobial activity against the oral pathogens (MIC--Minimal Inhibitory Concentrations values between 0.007 and 1.00 mg/mL). The essential oil from Coriandrum sativum inhibited all oral species with MIC values from 0.007 to 0.250 mg/mL, and MBC/MFC (Minimal Bactericidal/Fungicidal Concentrations) from 0.015 to 0.500 mg/mL. On the other hand the essential oil of C. articulatus inhibited 63.96% of S. sanguis biofilm formation. Through Scanning Eletronic Microscopy (SEM) images no changes were observed in cell morphology, despite a decrease in biofilm formation and changes on biofilm structure. Chemical analysis by Gas Chromatography-Mass Spectrometry (GC-MS) of the C. sativum essential oil revealed major compounds derivatives from alcohols and aldehydes, while Cyperus articulatus and Aloysia gratissima (EOs) presented mono and sesquiterpenes. In conclusion, the crude oil from C. articulatus exhibited the best results of antimicrobial activity e ability to control biofilm formation. The chemical analysis showed the presence of terpenes and monoterpenes such as a-pinene, a-bulnesene and copaene. The reduction of biofilms formation was confirmed from SEM images. The results of this research shows a great potential from the plants studied as new antimicrobial sources.

Chemistry, properties, and phylogenetic implications of the methylated carrageenans from red algae of the genus Areschougia (Areschougiaceae, Gigartinales, Rhodophyta)

The three Australian-endemic species comprising the genus Aresehougia have been examined to determine the structure of their nonfibrillar wall components. The polysaccharide extracted from the most widely distributed species, A. congesta (Turner) J. Agardh, was shown by compositional analyses, Fourier transform infrared (FTIR) spectroscopy, linkage analysis, and C-13-NMR spectroscopy to be a carrageenan composed predominantly of the repeating disaccharides 6'-O-methylcarrabiose 2,4'-disulfate, carrabiose 2,4-disulfate (the repeating unit of L-carrageenan), 4',6'-O-(1-carboxyethylidene)carrabiose 2-sulfate, and 6'-O-methylcarrabiose 2-sulfate. The carrageenan also contained small amounts of 4-linked Galp residues, some bearing methyl ether substitution at O-3 and some possibly bearing sulfate ester and/or glycosyl substitutions at O-3. The A. congesta carrageenan had unique rheological properties, its gels having some similarities to those of commercial iota -carrageenan but with the viscosity of commercial lambda -carrageenan. Polysaccharides from A. ligulata Harvey ex J. Agardh and A. stuartii Harvey were shown by constituent sugar and FTIR analyses to be sulfated galactans rich in mono-O-methylgalactose. The carrageenan structures of Areschougia spp. were consistent with those of the genera Rhabdonia, Erythroclonium, and Austroclonium, the other genera constituting the family Areschougiaceae.

Alpha-conotoxins: Nicotinic acetylcholine receptor antagonists as pharmacological tools and potential drug leads

Alpha-Conotoxins are small disulfide rich peptides from the venoms of marine cone snails. They target specific nicotinic acetylcholine receptor (nAChR) subtypes with high affinity and potency and are therefore valuable as neurophamacological probes and potential drug leads. This article gives a general overview of the chemical and biological features of alpha -conotoxins, including their pharmacology, binding interactions and structure. A detailed analysis of recently reported three-dimensional structures from members of different subfamilies of the alpha -conotoxins, including those with 3/5, 4/3, 4/6 and 4.7 spacings of their two intracysteine loops is given. The structures are generally well defined and represent useful frameworks for the display of amino acid residues to target molecules.

Syntheses of polycationic dendrimers on lipophilic peptide core for complexation and transport of oligonucleotides

Synthesis of novel polycationic lipophilic peptide core(s) was accomplished and these agents successfully transfected human retinal pigment epithelium cells with ODN1 upon complexation with the oligonucleotide. The level of transfection was indirectly measured by the decreased production of the protein hVEGF (human vascular endothelial growth factor) in comparison to the transfection agent cytofectin GSV(TM). (C) 2002 Elsevier Science Ltd. All rights reserved.

Sustainable drugs and global health care

Each day, Earth's finite resources are being depleted for energy, for material goods, for transportation, for housing, and for drugs. As we evolve scientifically and technologically, and as the population of the world rapidly approaches 7 billion and beyond, among the many issues with which we are faced is the continued availability of drugs for future global health care. Medicinal agents are primarily derived from two sources, synthetic and natural, or in some cases, as semi-synthetic compounds, a mixture of the two. For the developed world, efforts have been initiated to make drug production "greener", with milder reagents, shorter reaction times, and more efficient processing, thereby using less energy, and reactions which are more atom efficient, and generate fewer by-products. However, most of the world's population uses plants, in either crude or extract form, for their primary health care. There is relatively little discussion as yet, about the long term effects of the current, non-sustainable harvesting methods for medicinal plants from the wild, which are depleting these critical resources without concurrent initiatives to commercialize their cultivation. To meet future public health care needs, a paradigm shift is required in order to adopt new approaches using contemporary technology which will result in drugs being regarded as a sustainable commodity, irrespective of their source. In this presentation, several approaches to enhancing and sustaining the availability of drugs, both synthetic and natural, will be discussed, including the use of vegetables as chemical reagents, and the deployment of integrated strategies involving information systems, biotechnology, nanotechnology, and detection techniques for the development of medicinal plants with enhanced levels of bioactive agents.

Foodstuffs and medicines as legal categories in the EU and China. Functional foods as a borderline case

The thesis discusses the regulation of foodstuffs and medicines, and particularly the regulation of functional foods. Legal systems investigated are the EU and China. Both are members of the WTO and Codex Alimentarius, which binds European and Chinese rules together. The study uses three Chinese berries as case examples of how product development faces regulation in practice. The berries have traditional uses as herbal medicines. Europe and China have similar nutrition problems to be resolved, such as obesity, cardiovascular disease, and diabetes. The three berries might be suitable raw materials for functional foods. Consumer products with health-enhancing functions, such as lowering blood pressure, might legally be classifi ed either as foodstuffs or medicines. The classifi cation will depend on functions and presentation of the product. In our opinion, food and medicine regulation should come closer together so the classifi cation issue would no longer be an issue. Safety of both foodstuffs and medicines is strictly regulated. With medicines, safety is a more relative concept, where benefi ts of the product are compared to side-effects in thorough scientifi c tests and trials. Foods, on the other hand, are not allowed to have side-effects. Hygiene rules and rules on the use of chemicals apply. In China, food safety is currently at focus as China has had several severe food scandals. Newly developed foods are called novel foods, and are specifi cally regulated. The current European novel food regulation from 1997 treats traditional third country products as novel. The Chinese regulation of 2007 also defi nes novel foods as something unfamiliar to a Chinese consumer. The concepts of novel food thus serve a protectionist purpose. As regards marketing, foods are allowed to bear health claims, whereas medicines bear medicinal claims. The separation is legally strict: foods are not to be presented as having medicinal functions. European nutrition and health claim regulation exists since 2006. China also has its regulation on health foods, listing the permitted claims and how to substantiate them. Health claims are allowed only on health foods. The European rules on medicines include separate categories for herbal medicines, traditional herbal medicines, and homeopathic medicines, where there are differing requirements for scientifi c substantiation. The scientifi c and political grounds for the separate categories provoke criticism. At surface, the Chinese legal system seems similar to the European one. To facilitate trade, China has enacted modern laws. Laws are needed as the country moves from planned economy to market economy: ‘rule of law’ needs to replace ‘rule of man’. Instead of being citizens, Chinese people long were subordinates to the Emperor. Confucius himself advised to avoid confl ict. Still, Chinese people do not and cannot always trust the legal system, as laws are enforced in an inconsistent manner, and courts are weak. In China, there have been problems with confl icting national and local laws. In Europe, the competence of the EU vs. the competence of the Member States is still not resolved, even though the European Commission often states that free trade requires harmonisation. Food and medicine regulation is created by international organisations, food and medicine control agencies, standards agencies, companies and their organisations. Regulation can be divided in ‘hard law’ and ‘soft law’. One might claim that hard law is in crisis, as soft law is gaining importance. If law is out of fashion, regulation certainly isn’t. In the future, ‘law’ might mean a process where rules and incentives are created by states, NGOs, companies, consumers, and other stakeholders. ‘Law’ might thus refer to a constant negotiation between public and private actors. Legal principles such as transparency, equal treatment, and the right to be heard would still be important.

Composition of Hawthorn (Crataegus spp.) Fruits and Leaves and emblic Leafflower (Phyllanthus emblica) Fruits

Hawthorn (Crataegus sp.) is widely distributed in the northern hemisphere (Asia, Europe and North America). It has been used as a medicinal material and food for hundreds of years both in Europe and in China. Clinical investigations and other research suggest that extracts of hawthorn fruits and leaves have multiple health effects including hypolipidaemic, anti-atherosclerotic, hypotensive, cardioprotective and blood vessel relaxing activities. Hawthorn fruit extracts have also displayed antioxidant and radical scavenging activities. Emblic leafflower fruit (Phyllanthus emblica) is widely used in Chinese and Indian traditional medicine. It has been found to have anti-cancer, hypoglycaemic and hypolipidaemic activities as well as cardioprotective effects and antioxidant activity. The fruit is currently used as a functional food targeted at obese people in China. Phenolic compounds, procyanidins (PCs), flavonols and C-glycosyl flavones in hawthorn and hydrolysable tannins in emblic leafflower fruits are considered among the major bioactive compounds in these berries. Moreover, hawthorn and emblic leafflower fruits are rich in vitamin C, triterpenoids, fruit acids, sugar alcohols and some other components with beneficial effects on the health of human beings. The aim of the thesis work was to characterise the major phenolic compounds in hawthorn fruits and leaves and emblic leafflower fruits as well as other components contributing to the nutritional profile and sensory properties of hawthorn fruits. Differences in the content and compositional profile of the major phenolic compounds, sugars, acids and sugar alcohols within various origins and species of hawthorn were also investigated. Acids, sugars and sugar alcohols in the fruits of different origins/cultivars belonging to three species (C. pinnatifida, C. brettschneideri and C. scabrifolia) of hawthorn were analysed by gas chromatography (GC-FID) and mass spectrometry (Publication I). Citric acid, quinic acid, malic acid, fructose, glucose, sorbitol and myo-inositol were found in all the subspecies. Sucrose was present only in C. scabrifolia and three cultivars of C. pinnatifida var. major. Forty-two phenolic compounds were identified/tentatively identified in fruits of C. pinnatifida var. major by polyamide column chromatography combined with high-performance liquid chromatograph-electrospray ionisation mass spectrometry (HPLC-ESI-MS) (Publication II). Ideain, chlorogenic acid, procyanidin (PC) B2, (-)-epicatechin, hyperoside and isoquercitrin were the major phenolic components identified. In addition, 35 phenolic compounds were tentatively identified based on UV and mass spectra. Eleven major phenolic compounds (hyperoside, isoquercitrin, chlorogenic acid, ideain, (-)-epicatechin, two PC dimers, three PC trimers and a PC dimer-hexoside) were quantified in the fruits of 22 cultivars/origins of three species of Chinese hawthorn by HPLC-ESI-MS with single ion recording function (SIR) (Publication III). The fruits of the hawthorn cultivars/origins investigated fell into two groups, one rich in sugars and flavonols, the other rich in acids and procyanidins. Based on the compositional features, different biological activities and sensory properties may be expected between cultivars/origins of the two groups. The results suggest that the contents of phenolic compounds, acids, sugars and sugar alcohols may be used as chemotaxonomic information distinguishing the hawthorn species from each other. Phenolic compounds in fruits and leaves of C. grayana and their changes during fruit ripening/harvesting were investigated using HPLC-UV-ESI-MS (Publication IV). (-)-Epicatechin, PC B2 and C1, hyperoside and a quercetin-pentoside were the major phenolic compounds in both fruits and leaves. Three C-glycosyl flavones (a luteolin-C-hexoside, a methyl luteolin-C-hexoside and an apigenin-C-hexoside) were present in leaves in abundance, but only at trace levels in fruits. Ideain and 5-O-caffeoylquinic acid were found in fruits only. Additionally, eleven phenolic compounds were identified/tentatively identified in both leaves and fruits (three B-type PC trimers, two B-type PC tetramers, a quercetin-rhamnosylhexoside, a quercetin-pentoside, a methoxykaempferol-methylpentosylhexoside, a quercetin-hexoside acetate, a methoxykaempferol-pentoside, chlorogenic acid and an unknown hydroxycinnamic acid derivative). The total content of phenolic compounds reached the highest level by the end of August in fruits and by the end of September in leaves. The compositional profiles of phenolic compounds in fruits and leaves of C. grayana were different from those of C. pinnatifida, C. brettschneideri, C. scabrifolia, C. pinnatifida. var. major, C. monogyna, C. laevigata and C. pentagyna. Phenolic compounds in emblic leafflower fruits were characterised by Sephadex LH-20 column chromatography combined with HPLC-ESI-MS (Publication V). A mucic acid gallate, three isomers of mucic acid lactone gallate, a galloylglucose, gallic acid, a digalloylglucose, putranjivain A, a galloyl-HHDP-glucose, elaeocarpusin and chebulagic acid represented the major phenolic compounds in fruits of emblic leafflower. In conclusion, results of this study significantly increase the current knowledge on the key bioactive and nutritional components of hawthorn and emblic leafflower fruits. These results provide important information for research on the mechanism responsible for the health benefits of these fruits.

How Learning Styles, Chemistry Attitudes and Experiences, Confidence, and Demographics Correlate with Academic Success in First and Second Year Chemistry Courses

At Brock University, the Faculty of Mathematics and Science currently has one of the highest percentages of students on academic probation, with many students reporting the most difficulty with Introductory Chemistry in first year and Organic Chemistry in second year. To identify strategies to improve students' performance and reduce the number of students on academic probation, a multi-year research project was undertaken involving several chemistry courses. Students were asked to complete three questionnaires, and provide consent to obtain their final Chemistry grade from the Registrar's Office. Research began at the end of the 2007-08 academic year with CHEM IPOO, and in the 2008-09 academic year, students in the larger CHEM IF92 Introductory Chemistry course were invited to participate in this research near the beginning of the academic year. Students who went on to take second year Organic and Analytical Chemistry were asked to complete these questionnaires in each second year course. The three questionnaires included the Kolb Learning Styles Inventory (Kolb, 1984) modified to include specific reference to Chemistry in each question, Dalgety, ColI, and Jones' (2002) Chemistry Attitudes and Experiences Questionnaire (CAEQ), and lastly, a demographic survey. Correlations were found between learning style and academic success; concrete learners were not as successful as abstract learners. Differences were noted between females and males with respect to learning styles, academic success, and confidence. Several differences were also noted between those who are the First in the Family to attend university and those who are not First in the Family to attend university.

Quantities, units and symbols in physical chemistry, 3rd edition

The first IUPAC Manual of Symbols and Terminology for Physicochemical Quantities and Units (the Green Book) of which this is the direct successor, was published in 1969, with the object of 'securing clarity and precision, and wider agreement in the use of symbols, by chemists in different countries, among physicists, chemists and engineers, and by editors of scientific journals'. Subsequent revisions have taken account of many developments in the field, culminating in the major extension and revision represented by the 1988 edition under the simplified title Quantities, Units and Symbols in Physical Chemistry. This 2007, third edition, is a further revision of the material which reflects the experience of the contributors with the previous editions. The book has been systematically brought up to date and new sections have been added. It strives to improve the exchange of scientific information among the readers in different disciplines and across different nations. In a rapidly expanding volume of scientific literature where each discipline has a tendency to retreat into its own jargon this book attempts to provide a readable compilation of widely used terms and symbols from many sources together with brief understandable definitions. This is the definitive guide for scientists and organizations working across a multitude of disciplines requiring internationally approved nomenclature.

Macrocyclic aromatic polysulfones and sulfide-sulfones: synthesis and structural characterisation of molecular pentagons and rectangles

Cyclo-condensation of arylenedithiols with bis(4-chlorophenylenesulfone)s under pseudo-high-dilution conditions affords macrocyclic aromatic sulfide-sulfones which are readily oxidised to all-sulfone-linked macrocycles. The cyclic pentamer of poly(1,4-phenylenesulfone) and cyclic dimer of poly(1,4-phenylenesulfonyl-4,4'-biphenylenesulfone) have been isolated and characterised.

Supramolecular aggregates between carboxylate anions and an octaaza macrocyclic receptor

The 28-membered octaazamacrocycle Me-2[28]py(2)N(6) was used as a receptor for the molecular recognition of aromatic and aliphatic carboxylate substrates. The receptor-substrate binding behaviour of (H6Me2[28]py(2)N(6))(6+) with an aliphatic (-O2C(CH2)(n)CO2-, n=0 to 4) and an aromatic (phthalate, isophthalate, terephthalate, 4,4'-dibenzoate, benzoate, 3- and 4-nitrobenzoate) series of carboxylate anions was evaluated by H-1 NMR spectroscopy (carried out in DMSO-d(6) at 300 K). Two association constants were found for most of the studied cases, except for 3- and 4-nitrobenzoate for which only K-1 was determined. For oxalate, malonate, benzoate and dibenzoate anions only the beta(2) constants could be obtained. The values of the first association constant cover a range from 2.86 to 3.69 (log units), and the second stepwise constant from 2.15 to 2.89 (also in log units). No special selectivity was found but the highest values were determined for adipate and the lowest for the monoprotic 3- and 4-nitrobenzoates. Single crystal X-ray structures of H6Me2[28]py(2)N(6)(6+) with terephthalate, 1, and 4,4'-dibenzoate (2) were determined showing supramolecular entities with general formula (H6Me2[28]py(2)N(6)).(substrate)(2)(PF6)(2).4H(2)O. These anions are the building blocks of an extensive 3-D network of hydrogen bonds.