Use in Synthesis of Microbial Arene Oxidation Products

Abstract This thesis is concerned with microbially derived cis-3,5-cyclohexadiene-1,2- dihydroxy-1-carboxylic acid and its iron tricarbonyl derivatives as precursors for the efficient and practical synthesis of useful products. The opening chapter consists of a review of the biocatalytic cis-dihydroxylation process including its mechanism and applications in synthesis. In a Chapter 2 the utility of cyclohexadiene iron tricarbonyl complexes to date is outlined, with particular focus on their preparation and reactivity. Synthetic routes towards the synthesis of the natural products gabaculine and carbazole alkaloids are described, followed by the preparation of tarniflu and general methods of decomplexation. Chapter 3 presents the synthesis of novel iron tricarbonyl complexes and studies on their reactivity are disclosed. (Figure A.) Chapter 4 describes the formation of a new rearrangement product of the acetonide protected iron tricarbonyl complexes. In order to validate this process, independent studies with labelled compounds have been employed. Following Myers' procedure for microbial oxidation of p-deutero-benzoic acid, quantities of a novel deutero-diol product were successfully prepared and used to elucidate the mechanism of the rearrangement process. (Figure B) In Chapter 5 the formation of the f]5 cyclohexadienyl complexes is discussed followed by the outcome of the nucleophilic addition products. Chapter 7 provides detailed specific and general procedures for the synthesis of the compounds described within this thesis, along with their characterisation data. The appendices provide analytical support to this thesis and list of publications. Each chapter includes a separate discussion of the results and Chapter 6 provides an overall summary and suggestions for possible future work.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A cobalt complex of a microbial arene oxidation product

We report the first synthesis of a cobalt Cp diene complex wherein the diene is derived by microbial dearomatising dihydroxylation of an aromatic ring. The complex has been characterised crystallographically and its structure is compared to that of an uncomplexed diene precursor

Evaluation of retinal nerve fibre layer, optic nerve head, and macular ganglion cell analysis measurements for early glaucoma detection using spectral domain optical coherence tomography

Background: Glaucoma is the leading cause of irreversible blindness worldwide. It is very important to diagnose glaucoma in early stages so that timely management can be done. Spectral domain optical coherence tomography (SD-OCT), is a newer device which helps to diagnose glaucoma early. The aim of our study was to evaluate the RNFL, ONH, and mGCA (GCL+IPL) measurements for early glaucoma detection using spectral domain optical coherence tomography (SD-OCT).Methods: Total 30, POAG (primary open angle glaucoma) suspects were compared with 30 normal controls. The Cirrus HD-OCT optic disc cube 200 × 200 protocol was used to measure ONH, RNFL and macular parameters.Results: The average cpRNFL thickness of all quadrants was significantly lower in POAG suspects, (84.13±7.42 μm versus 103.85±8.95 μm, p<0.001). The superior GCL+IPL thickness of POAG suspects and controls was 75.75±2.60 μm and 80.05±1.74 μm, respectively, (p<0.001). The inferior GCL+IPL thickness of POAG suspects and controls was 75.98±2.59 μm and 80.00±1.79 μm, respectively, (p<0.001).Conclusions: The SD-OCT is an important device to diagnose POAG suspects, early. The GCA measurements and average RNFL (especially superior and inferior) measurements, both are equally good to discriminate between glaucoma suspects and normal controls

Determination of genotype differences through restriction endonuclease in Camels (Camelus dromedarius)

Tyrosinase gene or C locus has long been implicated in the coat colour determination. This gene a copper-containing enzyme located on chromosome 11q14.3 is expressed in melanocytes and controls the major steps in pigment production. In camel, C locus a restriction site provoked by the T variant of the mutation was used in a special restriction fragment length polymorphism analysis (PCR-RFLP) for genotyping of camels from six different Pakistani camel breeds (Marecha, Dhatti, Larri, Kohi, Campbelpuri and Sakrai). Significant differences in the genotype frequency between the breeds were estimated. The Sakrai breed showed in comparison to other studied breeds a distinctly higher frequency of the homozygous with restriction genotype. The objective of the present study was to screen the camel breeds using modern genetic technique that have been so far classified on the basis of performance and tribal ownership.Keywords: Camel, genotype, restriction endonucleas

Tricarbonyliron(0) complexes of bio-derived η4 cyclohexadiene ligands: An approach to analogues of oseltamivir

AbstractWe have prepared novel [η4] and [η5]+ tricarbonyliron complexes from an unusual enantiopure cyclohexadiene ligand that possesses a quaternary stereocentre; this in turn is prepared through biotransformation of an aromatic ring. The cyclohexadiene ligand initially possessed two hydroxyl groups, both of which could be substituted with other functionality by means of an overall [η4] → [η5]+ → [η4] → [η5]+ → [η4] sequence. From six novel tricarbonyliron complexes which have been prepared, three have been characterised by x-ray crystallography. The reaction sequence we describe is potentially of relevance to the synthesis of analogues of the anti-influenza drug oseltamivir. In addition, the failure of an attempted addition of a bulky nitrogen nucleophile to an [η5]+ complex sheds light on the limits of reactivity for such additions. Thus, two bulky nucleophiles which are each known to add successfully to unencumbered [η5]+ complexes seemingly cannot be added sequentially to adjacent positions on the cyclohexadiene ligand

The enone motif of (+)-grandifloracin is not essential for 'anti-austerity' antiproliferative activity

AbstractWe report the synthesis and biological evaluation of three analogues of the natural product (+)-grandifloracin (+)-1. All three analogues exhibit enhanced antiproliferative activity against PANC-1 and HT-29 cells compared to the natural product. The retention of activity in an analogue lacking the enone functional group, 9, implies this structural element is not an essential part of the (+)-grandifloracin pharmacophore

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI