Efficient syntheses of benzothiazepines as antagonists for the mitochondrial sodium-calcium exchanger: Potential therapeutics for type II diabetes

Type II diabetes mellitus is a chronic metabolic disorder that can lead to serious cardiovascular, renal, neurologic, and retinal complications. While several drugs are currently prescribed to treat type II diabetes, their efficacy is limited by mechanism-related side effects (weight gain, hypoglycemia, gastrointestinal distress), inadequate efficacy for use as monotherapy, and the development of tolerance to the agents. Consequently, combination therapies are frequently employed to effectively regulate blood glucose levels. We have focused on the mitochondrial sodium-calcium exchanger (mNCE) as a novel target for diabetes drug discovery. We have proposed that inhibition of the mNCE can be used to regulate calcium flux across the mitochondrial membrane, thereby enhancing mitochondrial oxidative metabolism, which in turn enhances glucose-stimulated insulin secretion (GSIS) in the pancreatic beta-cell. In this paper, we report the facile synthesis of benzothiazepines and derivatives by S-alkylation using 2-aminobenzhydrols. The syntheses of other bicyclic analogues based on benzothiazepine, benzothiazecine, benzodiazecine, and benzodiazepine templates are also described. These compounds have been evaluated for their inhibition of mNCE activity, and the results from the structure-activity relationship (SAR) studies are discussed.

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon(1-3). With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses(4-9). As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve `health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.

Incorporating fishery observer data into an integrated catch-at-age and multiyear tagging model for estimating mortality rates and abundance

Tagging experiments are a useful tool in fisheries for estimating mortality rates and abundance of fish. Unfortunately, nonreporting of recovered tags is a common problem in commercial fisheries which, if unaccounted for, can render these estimates meaningless. Observers are often employed to monitor a portion of the catches as a means of estimating reporting rates. In our study, observer data were incorporated into an integrated model for multiyear tagging and catch data to provide joint estimates of mortality rates (natural and f ishing), abundance, and reporting rates. Simulations were used to explore model performance under a range of scenarios (e.g., different parameter values, parameter constraints, and numbers of release and recapture years). Overall, results indicated that all parameters can be estimated with reasonable accuracy, but that fishing mortality, reporting rates, and abundance can be estimated with much higher precision than natural mortality. An example of how the model can be applied to provide guidance on experimental design for a large-scale tagging study is presented. Such guidance can contribute to the successful and cost-effective management of tagging programs for commercial fisheries.

Evaluating methods for estimating rare events with zero-heavy data: a simulation model estimating sea turtle bycatch in the pelagic longline fishery

Estimating rare events from zero-heavy data (data with many zero values) is a common challenge in fisheries science and ecology. For example, loggerhead sea turtles (Caretta caretta) and leatherback sea turtles (Dermochelys coriacea) account for less than 1% of total catch in the U.S. Atlantic pelagic longline fishery. Nevertheless, the Southeast Fisheries Science Center (SEFSC) of the National Marine Fisheries Service (NMFS) is charged with assessing the effect of this fishery on these federally protected species. Annual estimates of loggerhead and leatherback bycatch in a fishery can affect fishery management and species conservation decisions. However, current estimates have wide confidence intervals, and their accuracy is unknown. We evaluate 3 estimation methods, each at 2 spatiotemporal scales, in simulations of 5 spatial scenarios representing incidental capture of sea turtles by the U.S. Atlantic pelagic longline fishery. The delta-log normal method of estimating bycatch for calendar quarter and fishing area strata was the least biased estimation method in the spatial scenarios believed to be most realistic. This result supports the current estimation procedure used by the SEFSC.

Aquacrops of Darbhanga District in north Bihar and their commercial significance

Darbhanga district in North Bihar is characterised by thick alluvial soil, moderately good rainfall, high humidity, ample sunshine and numerous water resources in the form of perennial rivers, tributaries, streams, lakes, ponds, pools and puddles. The aquacrops of this district include several species of commercially important fishes, aquatic cash crops such as makhana (Euryale ferox), singhara (Trapa spp.), lotus, lilly, Khubi etc. and molluscs. This paper highlights the commercial significance of these aquacrops and offers suggestions for their sustained development.

弱互模拟等价类算法改进

大量的硬件和软件系统广泛应用在一些重要的领域，在许多情况下错误和失效是不可接受的。需要提供方法来检验软硬件的正确性，增强我们对软硬件系统的信心。形式化验证提供了提高软硬件可靠性的方法。 互模拟等价类和弱互模拟等价类可以用来降低形式化验证中模型的规模。弱互模拟等价类有两种算法：一种是先计算迁移关系的自反传递闭包，然后调用互模拟等价类的算法。另一种是作为IGPTPartEF的一个特例，直接在原图上用划分精化的方法计算。针对这些计算弱互模拟等价类的算法，我们提出两种改进算法。 首先，我们观察到有些状态在划分精化的过程中不会被再次切分，可以事先将它们归类到一个组，在划分精化过程中以这些组为基本单位进行切分，可以在很大程度上减小算法花费的时间。我们用该思想给设计出了改进算法一。 然后，我们观察在Paige-Tarjan算法中引入了“处理比较小的一半”的思想来改进计算互模拟等价类的算法，它使得计算互模拟等价类的算法的时间复杂度从O(mn)（其中m是边数，n是顶点数）改进到O(mlgn)，而在前面所述的弱互模拟等价类算法中并没有引入“处理比较小的一半”。我们引入这一思想，设计出了改进算法二。 之后，我们设计实现了原型工具，并进行了数据实验来证实算法在时间上与原算法相比有明显改进。

模态逻辑公式为见证的互模拟等价判定

判定两个进程是否具有某种等价关系，是形式化验证的重要组成部分，很多种等价关系被定义出来以满足不同的验证需求，强互模拟等价和分支互模拟等价是其中两个重要的两种等价关系。强互模拟等价可以用HML(Hennessy-Milner Logic)逻辑刻画，分支互模 拟等价可以用HMLU(HML with Until)等逻辑刻画。两个模型不能强互模拟等价或者分支互模拟等价时，存在一个作为见证的相应逻辑描述的公式，该公式只能被其中一个模型满足，称之为诊断公式。诊断公式的意义在于有助于分析理解模型为什么不具有相应的等价关系，给出诊断公式是对判定算法有意义的扩充。修改后的PT(Paige-Tarjan)算法可以用于计算有限状态进程之间的强互模 拟等价关系，修改后的GV(Groote-Vaandrager)算法可以用于计算分支互模拟，对它们相应的扩充可以为不能强互模拟等价或分支互模拟等价的进程生成诊断公式。 主要工作如下：分析为强互模拟等价和分支互模拟等价生成诊断公式的方法。设计处理有限状态进程表达式并将其转化为标号迁移系统的算法。扩展PT 算法，使其适用于标号迁移系统，并在判定强互模拟等价的过程中为不能强互模拟的进程生成HML 描述的诊断公式。扩展GV 算法，使其能够在判定标号迁移系统上分支互模拟的同时，为不能分支互模拟的进程生成HMLU 描述的诊断公式。

弱互模拟等价类算法改进

大量的硬件和软件系统广泛应用在一些重要的领域，在许多情况下错误和失效是不可接受的。需要提供方法来检验软硬件的正确性，增强我们对软硬件系统的信心。形式化验证提供了提高软硬件可靠性的方法。 互模拟等价类和弱互模拟等价类可以用来降低形式化验证中模型的规模。弱互模拟等价类有两种算法：一种是先计算迁移关系的自反传递闭包，然后调用互模拟等价类的算法。另一种是作为IGPTPartEF的一个特例，直接在原图上用划分精化的方法计算。针对这些计算弱互模拟等价类的算法，我们提出两种改进算法。 首先，我们观察到有些状态在划分精化的过程中不会被再次切分，可以事先将它们归类到一个组，在划分精化过程中以这些组为基本单位进行切分，可以在很大程度上减小算法花费的时间。我们用该思想给设计出了改进算法一。 然后，我们观察在Paige-Tarjan算法中引入了“处理比较小的一半”的思想来改进计算互模拟等价类的算法，它使得计算互模拟等价类的算法的时间复杂度从O(mn)（其中m是边数，n是顶点数）改进到O(mlgn)，而在前面所述的弱互模拟等价类算法中并没有引入“处理比较小的一半”。我们引入这一思想，设计出了改进算法二。 之后，我们设计实现了原型工具，并进行了数据实验来证实算法在时间上与原算法相比有明显改进。

生成诊断公式的有限状态进程等价验证

分析有限状态进程互模拟等价判定技术,探讨了诊断公式的生成问题。给出了将有限状态进程转化为带标号的迁移系统,修改了Paige和Trajan求解最粗划分的算法,使其适用于带标号的迁移系统。给出生成Hennessy-Milner逻辑描述的诊断公式的算法,当两个进程不能互模拟时,产生两个诊断公式。算法的时间复杂度为O(mlogn),空间复杂度为O(m+n)。

Are American Youth Alienated From Organized Religion?

The purpose of the project is to research the shape and influence of religion and spirituality in the lives of U.S. adolescents; to identify effective practices in the religious, moral, and social formation of the lives of youth; to describe the extent to which youth participate in and benefit from the programs and opportunities that religious communities are offering to their youth; and to foster an informed national discussion about the influence of religion in youth's lives, in order to encourage sustained reflection about and rethinking of our cultural and institutional practices with regard to youth and religion.

Religion in the lives of American adolescents

The purpose of the project is to research the shape and influence of religion and spirituality in the lives of U.S. adolescents; to identify effective practices in the religious, moral, and social formation of the lives of youth; to describe the extent to which youth participate in and benefit from the programs and opportunities that religious communities are offering to their youth; and to foster an informed national discussion about the influence of religion in youth's lives, in order to encourage sustained reflection about and rethinking of our cultural and institutional practices with regard to youth and religion.

Religion and the life attitudes and self-images of American adolescents

The purpose of the project is to research the shape and influence of religion and spirituality in the lives of U.S. adolescents; to identify effective practices in the religious, moral, and social formation of the lives of youth; to describe the extent to which youth participate in and benefit from the programs and opportunities that religious communities are offering to their youth; and to foster an informed national discussion about the influence of religion in youth's lives, in order to encourage sustained reflection about and rethinking of our cultural and institutional practices with regard to youth and religion.

Investigation of catalyst effects in enantioselective copper- and rhodium-mediated transformations of α-diazocarbonyl compounds

This thesis describes the synthesis and reactivity of a series of α-diazocarbonyl compounds with particular emphasis on the use of copper-bis(oxazoline)-mediated enantioselective C–H insertion reactions leading to enantioenriched cyclopentanone derivatives. Through the use of additives, the enantioselectivity achieved with the copper catalysts for the first time reaches synthetically useful levels (up to 91% ee). Chapter one provides a comprehensive overview of enantioselective C–H insertions with α-diazocarbonyl compounds from the literature. The majority of reports in this section involve rhodium-catalysed systems with limited reports to date of asymmetric C–H insertion reactions in the presence of copper catalysts. Chapter two focuses on the synthesis and C–H insertion reactions of α-diazo-β-keto sulfones leading to α-sulfonyl cyclopentanones as the major product. Detailed investigation of the impact of substrate structure (both the sulfonyl substitutent and the substituent at the site of insertion), the copper source, ligand, counterion, additive and solvent was undertaken to provide an insight into the mechanistic basis for enantiocontrol in the synthetically powerful C–H insertion process and to enable optimisation of enantiocontrol and ligand design. Perhaps the most significant outcome of this work is the enhanced enantioselection achieved through use of additives, substantially improving the synthetic utility of the asymmetric C–H insertion process. In addition to the C–H insertion reaction, mechanistically interesting competing reaction pathways involving hydride transfer are observed. Chapter three reports the extension of the catalyst-additive systems, developed for C–H insertions with α-diazo-β-keto sulfones in chapter two, to C–H insertion in analogous α-diazo-β-keto phosphonate and α-diazo-β-keto ester systems. While similar patterns were seen in terms of ligand effects, the enantiopurities achieved for these reactions were lower than those in the cyclisations with analogous α-diazo-β-keto sulfones. Extension of this methodology to cyclopropanation and oxium ylide formation/[2,3]-sigmatropic rearrangement was also explored. Chapter four contains the full experimental details and spectral characterisation of all novel compounds synthesised in this project, while details of chiral stationary phase HPLC analysis and X-ray crystallography are included in the appendix.

Synthetic and mechanistic aspects of the reactions of α-diazosulfoxides

The research described in this thesis focuses, principally, on synthesis of stable α-diazosulfoxides and investigation of their reactivity under various reaction conditions (transition-metal catalysed, photochemical, thermal and microwave) with a particular emphasis on the reactive intermediates and mechanistic aspects of the reaction pathways involved. In agreement with previous studies carried out on these compounds, the key reaction pathway of α-diazosulfoxides was found to be hetero-Wolff rearrangement to give α-oxosulfine intermediates. However, a competing reaction pathway involving oxygen migration from sulfur to oxygen was also observed. Critically, isomerisation of α-oxosulfine stereoisomers was observed directly by 1H NMR spectroscopy in this work and this observation accounts for the stereochemical outcomes of the various cycloaddition reactions, whether carried out with in situ trapping or with preformed solutions of sulfines. Furthermore, matrix isolation experiments have shown that electrocyclisation of α-oxosulfines to oxathiiranes takes place and this verifies the proposed mechanisms for enol and disulfide formation. The introductory chapter includes a brief literature review of the synthesis and reactivity of α-diazosulfoxides prior to the commencement of research in this field by the Maguire group. The Wolff rearrangement is also discussed and the characteristic reactions of a number of reactive intermediates (sulfines, sulfenes and oxathiiranes) are outlined. The use of microwave-assisted organic synthesis is also examined, specifically, in the context of α-diazocarbonyl compounds as substrates. The second chapter describes the synthesis of stable monocyclic and bicyclic lactone derivatives of α-diazosulfoxides from sulfide precursors according to established experimental procedures. Approaches to precursors of ketone and sulfimide derivatives of α-diazosulfoxides are also described. The third chapter examines the reactivity of α-diazosulfoxides under thermal, microwave, rhodium(II)-catalysed and photochemical conditions. Comparison of the results obtained under thermal and microwave conditions indicates that there was no evidence for any effect, other than thermal, induced by microwave irradiation. The results of catalyst studies involving several rhodium(II) carboxylate and rhodium(II) carboxamidate catalysts are outlined. Under photochemical conditions, sulfur extrusion is a significant reaction pathway while under thermal or transition metal catalysed conditions, oxygen extrusion is observed. One of the most important observations in this work was the direct spectroscopic observation (by 1H NMR) of interconversion of the E and Z-oxosulfines. Trapping of the α-oxosulfine intermediates as cycloadducts by reaction with 2,3-dimethyl-1,3-butadiene proved useful both synthetically and mechanistically. As the stereochemistry of the α-oxosulfine is retained in the cycloadducts, this provided an ideal method for characterisation of this key feature. In the case of one α-oxosulfine, a novel [2+2] cycloaddition was observed. Preliminary experiments to investigate the reactivity of an α-diazosulfone under rhodium(II) catalysis and microwave irradiation are also described. The fourth chapter describes matrix isolation experiments which were carried out in Rühr Universität, Bochum in collaboration with Prof. Wolfram Sander. These experiments provide direct spectroscopic evidence of an α-oxosulfine intermediate formed by hetero-Wolff rearrangement of an α-diazosulfoxide and subsequent cyclisation of the sulfine to an oxathiirane was also observed. Furthermore, it was possible to identify which stereoisomer of the α-oxosulfine was present in the matrix. A preliminary laser flash photolysis experiment is also discussed. The experimental details, including all spectral and analytical data, are reported at the end of each chapter. The structural interpretation of 1H NMR spectra of the cycloadducts, described in Chapter 3, is discussed in Appendix I.

Optimisation of chemoenzymatic processes in asymmetric synthesis

This thesis describes the optimisation of chemoenzymatic methods in asymmetric synthesis. Modern synthetic organic chemistry has experienced an enormous growth in biocatalytic methodologies; enzymatic transformations and whole cell bioconversions have become generally accepted synthetic tools for asymmetric synthesis. Biocatalysts are exceptional catalysts, combining broad substrate scope with high regio-, enantio- and chemoselectivities enabling the resolution of organic substrates with superb efficiency and selectivity. In this study three biocatalytic applications in enantioselective synthesis were explored and perhaps the most significant outcome of this work is the excellent enantioselectivity achieved through optimisation of reaction conditions improving the synthetic utility of the biotransformations. In the first chapter a summary of literature discussing the stereochemical control of baker’s yeast (Saccharomyces Cerevisae) mediated reduction of ketones by the introduction of sulfur moieties is presented, and sets the work of Chapter 2 in context. The focus of the second chapter was the synthesis and biocatalytic resolution of (±)-trans-2-benzenesulfonyl-3-n-butylcyclopentanone. For the first time the practical limitations of this resolution have been addressed providing synthetically useful quantities of enantiopure synthons for application in the total synthesis of both enantiomers of 4-methyloctanoic acid, the aggregation pheromone of the rhinoceros beetles of the genus Oryctes. The unique aspect of this enantioselective synthesis was the overall regio- and enantioselective introduction of the methyl group to the octanoic acid chain. This work is part of an ongoing research programme in our group focussed on baker’s yeast mediated kinetic resolution of 2-keto sulfones. The third chapter describes hydrolase-catalysed kinetic resolutions leading to a series of 3-aryl alkanoic acids. Hydrolysis of the ethyl esters with a series of hydrolases was undertaken to identify biocatalysts that yield the corresponding acids in highly enantioenriched form. Contrary to literature reports where a complete disappearance of efficiency and, accordingly enantioselection, was described upon kinetic resolution of sterically demanding 3-arylalkanoic acids, the highest reported enantiopurities of these acids was achieved (up to >98% ee) in this study through optimisation of reaction conditions. Steric and electronic effects on the efficiency and enantioselectivity of the biocatalytic transformation were also explored. Furthermore, a novel approach to determine the absolute stereochemistry of the enantiopure 3-aryl alkanoic acids was investigated through combination of co-crystallisation and X-ray diffraction linked with chiral HPLC analysis. The fourth chapter was focused on the development of a biocatalytic protocol for the asymmetric Henry reaction. Efficient kinetic resolution in hydrolase-mediated transesterification of cis- and trans- β-nitrocyclohexanol derivatives was achieved. Combination of a base-catalysed intramolecular Henry reaction coupled with the hydrolase-mediated kinetic resolution with the view to selective acetylation of a single stereoisomer was investigated. While dynamic kinetic resolution in the intramolecular Henry was not achieved, significant progress in each of the individual elements was made and significantly the feasibility of this process has been demonstrated. The final chapter contains the full experimental details, including spectroscopic and analytical data of all compounds synthesised in this project, while details of chiral HPLC analysis are included in the appendix. The data for the crystal structures are contained in the attached CD.