Investigations of the biosynthesis and biomimetic synthesis of bioactive natural products

This thesis describes work towards the biomimetic synthesis and understanding the biosynthesis of two families of natural products: prodiginines and quartromicins. Prodiginines are a large family of red pigmented tripyrrole antibiotics. Although they have not been used clinically, the promising anti-cancer, immunosuppressive and antimalarial activity they display at non-toxic doses has generated renewed interest in their utilisation. The synthesis of an analogue of the proposed pyrrole-2-carboxyl-RedO intermediate in prodiginine biosynthesis has been achieved. The resulting NAC thioester and analogues of it have been used to investigate the prodiginine biosynthetic pathway in Streptomyces coelicolor, and to examine the production of prodiginine analogues by mutasynthesis. Quartromicins, novel anti-viral antibiotics, are a structurally unique group of spirotetronate natural products produced by Amycolatopsis species. They are unusual symmetric macro cyclic compounds which possess a 32-membered carbocyclic structure with four spirotetronic acid units connected by enone or dienone linkers in a head-to-tail fashion. These macrocyclic compounds are intriguing because they have alternating endo- and exo- spirotetronic acid units, with the opposite "comers" being identical. Although the quartromicins have therapeutic potential, very little is known about their biosynthesis. In this research a biosynthetic pathway to the quartromicins has been proposed based on hypothetical pathways to related natural products. The synthesis of the two putative key intermediates in quartromicin biosynthesis has been achieved. An improved method for the synthesis of exomethylene tetronates has been developed, and novel rearrangements have been discovered. The two putative key intermediates have been used to investigate the biomimetic synthesis of the carbon skeleton of the quartromicin algycone, and mass spectrometric evidence for formation of homo- and heterodimers, and a heterotetramer of the key intermediates has been obtained

Jane Montgomery Griffiths' Theatrical Poetics

As scholar of the Classics and drama studies, Jane Montgomery Griffiths has devoted much of her artistic practice to interpreting the voices of women who have either been censored or misinterpreted throughout history. Montgomery Griffiths has been celebrated for her writing of, and solo performances in, productions such as Razing Hypatia and Sappho in 9 Fragments . With her experience of theatrically exploring female desire, sexuality and intellectual contribution, it is understandable that Montgomery Griffiths was attracted to Dorothy Porter's verse novel Wild Surmise written in the Sapphic tradition with lyrics mediating on desire, exploration and loss

Reconstructing the lifetime movements of ancient people: a Neolithic case study from southern England

A new procedure is described in which combined lead and strontium isotope analysis of archaeological human dental tissues can be used to comment on the lifetime movements of individuals. A case study is presented of four Neolithic burials – an adult female and three juveniles – from a shared burial pit excavated at Monkton-up-Wimbourne, Dorset. It is demonstrated that the adult's place of origin was at least 80km to the north-west in the area of the Mendips. It is also shown that all three juveniles moved over significant distances during their lives

Investigations of the biosynthesis and biomimetic synthesis of bioactive natural products

This thesis describes work towards the biomimetic synthesis and understanding the biosynthesis of two families of natural products: prodiginines and quartromicins. Prodiginines are a large family of red pigmented tripyrrole antibiotics. Although they have not been used clinically, the promising anti-cancer, immunosuppressive and antimalarial activity they display at non-toxic doses has generated renewed interest in their utilisation. The synthesis of an analogue of the proposed pyrrole-2-carboxyl-RedO intermediate in prodiginine biosynthesis has been achieved. The resulting NAC thioester and analogues of it have been used to investigate the prodiginine biosynthetic pathway in Streptomyces coelicolor, and to examine the production of prodiginine analogues by mutasynthesis. Quartromicins, novel anti-viral antibiotics, are a structurally unique group of spirotetronate natural products produced by Amycolatopsis species. They are unusual symmetric macro cyclic compounds which possess a 32-membered carbocyclic structure with four spirotetronic acid units connected by enone or dienone linkers in a head-to-tail fashion. These macrocyclic compounds are intriguing because they have alternating endo- and exo- spirotetronic acid units, with the opposite "comers" being identical. Although the quartromicins have therapeutic potential, very little is known about their biosynthesis. In this research a biosynthetic pathway to the quartromicins has been proposed based on hypothetical pathways to related natural products. The synthesis of the two putative key intermediates in quartromicin biosynthesis has been achieved. An improved method for the synthesis of exomethylene tetronates has been developed, and novel rearrangements have been discovered. The two putative key intermediates have been used to investigate the biomimetic synthesis of the carbon skeleton of the quartromicin algycone, and mass spectrometric evidence for formation of homo- and heterodimers, and a heterotetramer of the key intermediates has been obtained.EThOS - Electronic Theses Online ServiceEngineering and Physical Sciences Research Council (EPSRC)GBUnited Kingdo

An isotopic investigation into the origins and husbandry of Mid-Late Bronze Age cattle from Grimes Graves, Norfolk

Bioarchaeological evidence suggests that the site of Grimes Graves, Norfolk, characterised by the remains of several hundred Late Neolithic flint mineshafts, was a permanently settled community with a mixed farming economy during the Mid-Late Bronze Age (c. 1400 BCE – c. 800 BCE). The aim of this study was to investigate, through isotope ratio analysis (87Sr/86Sr, δ13C and δ18O), the origins and husbandry of Bronze Age cattle (Bos taurus) excavated from a mineshaft known as the “1972 shaft”. Strontium isotope ratios from the molar enamel of ten Grimes Graves cattle were compared with eight modern animals from the Chillingham Wild White cattle herd, Northumberland. The range of 87Sr/86Sr values for the modern cattle with known restricted mobility was low (0.00062) while the values for the Grimes Graves cattle varied much more widely (range = 0.00357) and suggest that at least five of the cattle were not born locally. Two of these animals were likely to have originated at a distance of ≥ 150 km. Intra-tooth δ13C profiles for eight of the Grimes Graves cattle show higher δ13C values compared to those of Early Bronze Age cattle from central England. Most of these profiles also display pronounced shifts in δ13C during the period of enamel formation. One possible interpretation is that the cattle were subject to dietary change resulting from movement between habitats with different vegetation δ13C values. More comparative data, both archaeological and modern, is required to validate this interpretation. The multi-isotope approach employed in this study suggests that certain cattle husbandry and/or landscape management practices may have been widely adopted throughout central Britain during the Mid-Late Bronze Age

Provenancing antiquarian museum collections using multi-isotope analysis

Many of the most significant archaeological sites in Europe were excavated by antiquarians over one hundred years ago. Modern museum collections therefore frequently contain human remains that were recovered during the nineteenth and early twentieth centuries. Here we apply multi-isotope analysis (87Sr/86Sr, δ18O, δ13C, δ15N) and 14C dating to evaluate the provenance of human remains within a collection that is thought to have been recovered from one of the most important archaeological sites in Britain. Excavated in 1910, the site of Coldrum in Kent is a megalithic burial monument that may be one of the earliest sites associated with the transition to farming in Britain. The interpretation of this site is therefore key to understanding how agriculture began. Using isotope analysis we show that although the human skeletal collections attributed to Coldrum do contain some of the earliest dated Neolithic human remains in Britain, they also contain the remains of individuals of fifth to seventh centuries AD date. We evaluate subsistence and mobility patterns of early Neolithic populations and provide new information about the origins of those individuals in the collection that date to the fifth to seventh centuries AD. We demonstrate the utility of employing isotope analysis to provide direct and independent information about the provenance of human remains in museum collections