A combinatorial approach to the chemical synthesis and biological evaluation of 3,4,5-trisubstiituted furan-2(5H)-ones

Many important natural products contain the furan-2(5H)-one structure. The structure of this molecule lends itself to manipulation using combinatorial techniques due to the presence of more than one site for the attachment of different suhstituents. By developing different reaction schemes at the three sites available for attachment on the furan-2(5H)-one scaffold, combinatorial chemistry techniques can be employed to assemble libraries of novel furan 2(5H)-ones. These libraries can then be entered into various biological screening programmes. This approach will enable a vast diversity or compounds to be examined, in the hope or finding new biologically active Iead structures. The work in this thesis has investigated the potential that combinatorial chemistry has in the quest for new biologically active lead structures based on the furan-2(5H)-one structure. Different reactions were investigated with respect to their suitability for inclusion in a library. Once sets of reactions at the various sites had been established, the viability of these reactions in the assembly of combinatorial libraries was investigated. Purification methods were developed, and the purified products entered into suitable biological screening tests. Results from some of these tests were optimised using structure activity relationships, and the resulting products re-screened. The screening tests performed were for anticancer and antimicrobial activity, cholecystokinin (CCK-B) antagonism and anti-inflammatory activity (in the quest for novel cyclo-oxygenase (COX-2) selective non-steroidal anti-inflammatory drugs). It has been shown that many reactions undergone by the furan-2(5H)-one structure are suitable for the assembly of a combinatorial library. Investigation into the assembly of different libraries has been carried out with initial screening results included. From this work, further investigation into combinatorial library assembly and structure activity relationships of screened reaction products can be undertaken.

Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries

Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic (DOS) libraries. Herein we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a DOS approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI Diversity and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity < 0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of DOS libraries with existing drugs or any other compound collection.

Long-finned pilot whale population diversity and structure in Atlantic waters assessed through biogeochemical and genetic markers

Acknowledgements. Cetacean samples were collected under the auspices of stranding monitoring programs run by the Sociedade Portuguesa de Vida Selvagem, the Coordinadora para o Estudio dos Mamíferos Mariños (supported by the regional government Xunta de Galicia), the UK Cetacean Strandings Investigation Programme and the Scottish Agriculture College Veterinary Science Division (jointly funded by Defra and the Devolved Governments of Scotland and Wales), the Marine Mammals Research Group of the Institute of Marine Research (Norway), the Museum of Natural History of the Faroe Islands and the International Fund for Animal Welfare Marine Mammal Rescue and Research Program (USA). The authors thank all the members of these institutions and organizations for their assistance with data and sample collection. S.S.M., P.M.F. and M.F. were supported by PhD grants from the Fundação para a Ciência e Tecnologia (POPH/FSE ref SFRH/BD/ 38735/ 2007, SFRH/BD/36766/2007 and SFRH/BD/30240/ 2006, respectively). A.L. was supported by a postdoctoral grant from the Fundação para a Ciência e Tecnologia (ref SFRH/BPD/82407/2011). The work related to strandings and tissue collection in Portugal was partially supported by the SafeSea project EEAGrants PT 0039 (supported by Iceland, Liechtenstein and Norway through the EEA Financial Mechanism), the MarPro project Life09 NAT/PT/000038 (funded by the European Union program LIFE+) and the project CetSenti FCT RECI/AAG-GLO/0470/2012 (FCOMP- 01-0124-FEDER-027472) (funded by the program COMPETE and the Fundação para a Ciência e Tecnologia). G.J.P. thanks the University of Aveiro and Caixa Geral de Depósitos (Portugal) for financial support. The authors acknowledge the assistance of the chemical analysts at Marine Scotland Science with the fatty acid analysis.

Long-finned pilot whale population diversity and structure in Atlantic waters assessed through biogeochemical and genetic markers

Acknowledgements. Cetacean samples were collected under the auspices of stranding monitoring programs run by the Sociedade Portuguesa de Vida Selvagem, the Coordinadora para o Estudio dos Mamíferos Mariños (supported by the regional government Xunta de Galicia), the UK Cetacean Strandings Investigation Programme and the Scottish Agriculture College Veterinary Science Division (jointly funded by Defra and the Devolved Governments of Scotland and Wales), the Marine Mammals Research Group of the Institute of Marine Research (Norway), the Museum of Natural History of the Faroe Islands and the International Fund for Animal Welfare Marine Mammal Rescue and Research Program (USA). The authors thank all the members of these institutions and organizations for their assistance with data and sample collection. S.S.M., P.M.F. and M.F. were supported by PhD grants from the Fundação para a Ciência e Tecnologia (POPH/FSE ref SFRH/BD/ 38735/ 2007, SFRH/BD/36766/2007 and SFRH/BD/30240/ 2006, respectively). A.L. was supported by a postdoctoral grant from the Fundação para a Ciência e Tecnologia (ref SFRH/BPD/82407/2011). The work related to strandings and tissue collection in Portugal was partially supported by the SafeSea project EEAGrants PT 0039 (supported by Iceland, Liechtenstein and Norway through the EEA Financial Mechanism), the MarPro project Life09 NAT/PT/000038 (funded by the European Union program LIFE+) and the project CetSenti FCT RECI/AAG-GLO/0470/2012 (FCOMP- 01-0124-FEDER-027472) (funded by the program COMPETE and the Fundação para a Ciência e Tecnologia). G.J.P. thanks the University of Aveiro and Caixa Geral de Depósitos (Portugal) for financial support. The authors acknowledge the assistance of the chemical analysts at Marine Scotland Science with the fatty acid analysis.

Diversity in a simple co-crystal: racemic and kryptoracemic behaviour.

The crystal structure containing (+/-)-3-methyl-2-phenylbutyramide with salicylic acid is the first example of a kryptoracemate co-crystal. It exhibits the first temperature mediated reversible single-crystal to single-crystal transition between two kryptoracemate forms, in addition to crystallising in another, racemic, form. Theoretical calculations and structural analysis reveal that there are only small differences in both energy and packing arrangements between the three forms. These results suggest that co-crystals can be an opportunity to investigate kryptoracemate behaviour.

Macroinvertebrate Community Composition and Diversity in Ephemeral and Perennial Ponds on Unregulated Floodplain Meadows in the UK

Ponds are common and abundant landscape features in temperate environments, particularly on floodplains where lateral connectivity with riverine systems persists. Despite their widespread occurrence and importance to regional diversity, research on the ecology and hydrology of temperate ephemeral and perennial floodplain ponds lags behind that of other shallow waterbodies. This study examines the aquatic macroinvertebrate diversity of 34 ponds (20 perennial and 14 ephemeral) on two unregulated riverine floodplain meadows in Leicestershire, UK. Perennial ponds supported nearly twice the diversity of ephemeral ponds. Despite frequent inundation of floodwater and connectivity with other floodplain waterbodies, ephemeral ponds supported distinct invertebrate communities when compared to perennial ponds. When the relative importance of physical and chemical, biological and spatial characteristics was examined, physical and chemical characteristics were found to account for more variation in community composition than biological or spatial variables. The results suggest that niche characteristics rather than neutral colonisation processes dominate the structure of invertebrate communities of floodplain ponds. The maintenance of pond networks with varying hydroperiod lengths and environmental characteristics should be encouraged as part of conservation management strategies to provide heterogeneous environmental conditions to support and enhance aquatic biodiversity at a landscape scale.

An investigation on benthic macro-invertebrates species diversity as bio-indicators of environmental health in Bahrekan Bay

The purpose of this study was to evaluate benthic macro-invertebrates species diversity as bio-indicators of environmental health in Bahrekan bay (in the Northwest of Persian gulf). Seasonal sediments sampling along 5 transects, 15 stations at 4 replicates (3 replicates for macrobenthos and 1 replicate for sediment analysis) was done from November 2008 to August 2009 by 0.025 m2 Van Veen grab sampler. Physical and chemical parameters of water, grain size analysis, %TOM and Ni and Va concentrations of sediments were assessed through four seasons. Macrobenthic communities after staining and sorting, using stereomicroscope have been identified. Their density in every station and every season calculated. For using of AMBI index, identified macrobenthos according to their sensitivity to stressors and pollutants, categorized into 5 ecological groups and for using of Bentix index categorized into 3 ecological groups. The diversity indices and indicators that showing ecological status were calculated. Also, the differences between physiochemical parameters of sea water, sediments TOM% and grain size, diversity indices in stations and seasons were recorded (P=0.05). The correlation coefficient determined for all parameters. According to the results of grain size analysis, bottom grain size categorized as clay. Highest percent of TOM was belong to autumn (36.39±.075) and lowest was belong to summer (19.01±0.51). Also there was positive correlation (p=0.01) between %TOM and %Clay that showing sediments with lowest size containing highest amounts of organic matters. Ni concentrations in sediments (87.80±21.25)mg/kg showed the amounts over than standards levels but Va concentrations in sediments (53.54±17.60)mg/kg showed the amounts lower than standards level. The highest density of macrobenthos was recorded for summer (8254±485) N/m2 and the lowest density was recorded for spring (3775±172)N/m2. The highest annual density was belong to mollusca (81%) and then polycheates (13%), Others (4%) and crustaceae (2%). The highest diversity was recorded for winter (Simpson index: 0.13±0.01, H':3.47±0.06) and the lowest diversity recorded for autumn (Simpson index: 0.16±0.01, H':3.17±0.06). in all stations, the highest amount of Shanon index was belong to T2S3 station in summer (4.11± 0.32) and the lowest amount was belong to T1S1 station in autumn (2.42± 0.41). The annual mean of Simpson diversity index: (0.15 ±0.04) and Shanon diversity index (3.36±0.03), illustrated that macrobenthos in Bahrekan bay have a good variation. The results of Brilluin and N1 (Number of equally common species) indices confirm the results of Simpson index. For study on the regions that diversity has a little difference between stations, with use of Ni index, the degree of differences could be better ono recognizable. According to the results of AMBI index in all seasons (autumn: 0.46±0.03; summer: 0.22±0.01; annual mean:0.31±0.01) and standards (0.0diversity was belong to the summer and the lowest amount of species diversity was belong to the autumn. With regarding to high species diversity in Bahrekan Bay, AMBI index present accurate assessment rather to Bentix index. AMBI can be used successfully in ecosystems like to study area for detecting the pollutant and disturbance recourses.

Irrigation with Treated Wastewater: Potential Impacts on Microbial Function and Diversity in Agricultural Soils

The reuse of treated wastewater could be a promising measure to attenuate the water scarcity burden. In agriculture, irrigation with wastewater may contribute to improve production yields, reduce the ecological footprint and promote socioeconomic benefits. However, it cannot be considered exempt of adverse consequences in environmental and human health. Apart from the introduction of some biological and chemical hazardous agents, the disturbance of the indigenous soil microbial communities and, thus, of vital soil functions impacting soil fertility may occur. The consequences of these disturbances are still poorly understood. This chapter summarises the physicochemical and microbiological alterations in soil resultant from irrigation with treated wastewater that are described in scientific literature. These alterations, which involve a high complexity of variables (soil, wastewater, climate, vegetal cover), may have impacts on soil quality and productivity. In addition, possible health risks may arise, in particular through the direct or indirect contamination of the food chain with micropollutants, pathogens or antibiotic resistance determinants. The current state of the art suggests that irrigation with treated wastewater may have a multitude of long-term implications on soil productivity and public health. Although further research is needed, it seems evident that the analysis of risks associated with irrigation with treated wastewater must take into account not only the quality of water, but other aspects as diverse as soil microbiota, soil type or the cultivated plant species.

Sexual selection in a tropical fruit fly : role of a plant derived chemical in mate choice

The specific mechanisms by which selective pressures affect individuals are often difficult to resolve. In tephritid fruit flies, males respond strongly and positively to certain plant derived chemicals. Sexual selection by female choice has been hypothesized as the mechanism driving this behaviour in certain species, as females preferentially mate with males that have fed on these chemicals. This hypothesis is, to date, based on studies of only very few species and its generality is largely untested. We tested the hypothesis on different spatial scales (small cage and seminatural field-cage) using the monophagous fruit fly, Bactrocera cacuminata. This species is known to respond to methyl eugenol (ME), a chemical found in many plant species and one upon which previous studies have focused. Contrary to expectation, no obvious female choice was apparent in selecting ME-fed males over unfed males as measured by the number of matings achieved over time, copulation duration, or time of copulation initiation. However, the number of matings achieved by ME-fed males was significantly greater than unfed males 16 and 32 days after exposure to ME in small cages (but not in a field-cage). This delayed advantage suggests that ME may not influence the pheromone system of B. cacuminata but may have other consequences, acting on some other fitness consequence (e.g., enhancement of physiology or survival) of male exposure to these chemicals. We discuss the ecological and evolutionary implications of our findings to explore alternate hypotheses to explain the patterns of response of dacine fruit flies to specific plant-derived chemicals.