Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2006. / Includes bibliographical references (leaves 113-121). Also available in electronic version.

Thesis (Ph. D.)--University of Idaho, 2006. / Abstract. "May 2006." Includes bibliographical references. Also available online in PDF format.

Malaria is one of the most prevalent diseases in Africa and the Plasmodium falciparum species is widely accepted as the most virulent, with a fatality rate of 15 – 20 % of reported cases of infection. While various treatments have been accepted into early stage clinical trials there has been little progress towards a proven vaccine. Pending a long term solution, endemic countries rely heavily on the development of innovative drugs with acute efficacy coupled with rapids mode of action. Until recently the rate of drug action has been measured by light microscopic examination of parasite morphology using blood slides of drug treated parasite cultures at regular time intervals. This technique is tedious and, most importantly, subject to interpretation with regards to distinguishing between viable and comprised parasite cells, thus making it impossible to objectively quantitate the rate of drug action. This study aimed to develop a series of bioassays using the calcein-acetoxymethyl and propidium iodide vitality probes which would allow the rate of drug action on Plasmodium falciparum malaria parasites to be assessed and ranked in relation to each other. A novel bioassay using these fluorescent vitality probes coupled with fluorescence microscopy was developed and optimized and allowed the rate of drug action on malaria parasites to be assessed i) rapidly (in relation to current assay techniques) and ii) in a semi-quantitative manner. Extrapolation to flow cytometry for improved quantification provided favourable rankings of drug killing rates in the pilot study, however, requires further development to increase throughput and approach the ultimate goal of producing a medium-throughput assay for rapidly assessing the rate of action of antimalarial drugs. Attempts to adapt the assay for use in a multiwell plate reader, as well as using ATP measurements as an indication of parasite vitality after drug treatment, was met with erratic results. The viability probes assay as it stands represents an improvement on other assay formats in terms of rapidity and quantification of live/compromised parasites in cultures.

Orientador: Lea Maria Leme Strini Velho / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Geociências / Made available in DSpace on 2018-08-15T22:44:01Z (GMT). No. of bitstreams: 1 Fioravanti_CarlosHenrique_D.pdf: 16620108 bytes, checksum: 91f81bcd902a0450d800acd337260969 (MD5) Previous issue date: 2010 / Resumo: Este trabalho expõe a diversidade de atores humanos e não-humanos - fungos, médicos, veterinários, camundongos, galinhas, cães, pacientes, pesquisadores acadêmicos, advogados, organizações não governamentais, empresários, diretores de agências de financiamento, assessores ad hoc, ministros, assessores de ministérios, jornalistas, vírus, bactérias e computadores - que se encontraram, se desencontraram, se conectaram (ou não) e se moveram em redes ora mais restritas, ora mais amplas, ao longo da construção do medicamento P-Mapa. As estratégias de ação adotadas pelos protagonistas também foram diversas. Inicialmente, o médico Odilon da Silva Nunes trabalhou durante quase 40 anos em um laboratório em sua própria casa, afastado dos centros formais de pesquisas científicas, para desenvolver e testar uma molécula que pudesse deter tumores, de acordo com sua própria hipótese sobre a origem do câncer. A pesquisa avançou por meio do trabalho coletivo de outros médicos e pesquisadores não-acadêmicos e acadêmicos que avaliaram a propriedades do composto de acordo com as regras convencionais de desenvolvimento de fármacos, ampliaram a escala de produção e o aplicaram experimentalmente para tratar um grupo restrito de pessoas com HIV/AIDS; por reconstituir as defesas naturais do organismo, o P-Mapa apresentou-se com uma rara versatilidade, a ponto de agir contra tumores, vírus, bactérias e protozoários em experimentos em modelos animais e em primeiros testes em seres humanos. Em seguida, sem lograr alianças com empresas que pudessem produzir o composto, o grupo se reorganizou, ampliou-se por meio de colaborações internacionais e concentrou a pesquisa sobre o medicamento em doenças infecciosas, especialmente as mais comuns em países em países pobres, como AIDS e tuberculose. Examinado por meio da Teoria Ator-Rede (TAR), o percurso do P-Mapa valoriza o papel dos mediadores para unir competências dispersas em torno de objetivos comuns de ganhos coletivos. A trajetória desse composto até o estágio inicial de testes em seres humanos ilustra estratégias inexploradas de produção de conhecimento científico no Brasil / Abstract: This work describes the diversity of human and non-humans actors - fungi, physicians, veterinarians, mice, chickens, dogs, patients, academic researchers, lawyers, non-governmental organizations, businessmen, funding agency heads, ad hoc referees, ministers, ministry officers, journalists, viruses, bacteria, and computers - who have met and separated, connected and split up, and moved into wider or narrower networks along the construction of the P-Mapa compound. The action strategies adopted by the protagonists were also diverse. Initially, the physician Odilon da Silva Nunes worked for almost 40 years in a private laboratory, away from formal science research centers, to develop and test a molecule that could block tumors, according to his own hypothesis about the origin of cancer. The research advanced through the collective work of other physicians and both non-academic and academic researchers who evaluated the compound's properties according to the regulation of drug development; they scaled up the production and tested the compound on a group of HIV-positive people. The P-Mapa, by rebuilding the body's natural defenses, showed a rare versatility, attacking tumors, viruses, bacteria and protozoa in experimental animal models and early testing on humans. Next, unable to forge alliances with pharmaceutical companies that could produce the compound, the research group reorganized, grew internationally and focused the research on infectious diseases, especially the most common in poor countries, such as AIDS and tuberculosis. Examined through Actor-Network Theory (ANT), the development of the P-Mapa highlights the role of mediators to bring together dispersed skills with common goals to achieve collective benefits. This compound's course from discovery to the early stage of human trials illustrates innovative ways to produce scientific knowledge in Brazil / Doutorado / Politica Cientifica e Tecnologica / Doutor em Política Científica e Tecnológica

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20002号 / 工博第4246号 / 新制||工||1657(附属図書館) / 33098 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 濵地 格, 教授 森 泰生, 教授 跡見 晴幸 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

No description available.

<p>CHS 828 is a cyanoguanidine with anti-tumour properties which has shown promising effects in several preclinical models. This thesis describes both preclinical and clinical studies aiming to investigate disease specific activity, clinical tolerability and efficacy of CHS 828.</p><p>In paper I we investigated CHS 828 activity in a cell line panel with human myeloma cells, three of these cell-lines were also tested in vivo using a hollow fibre rat-model. In paper II we investigated CHS 828 activity in primary human tumour samples from patients. CHS 828 showed an effect on all tumour cell types tested both the primary human tumour samples and the myeloma cell lines. Notably, CHS 828 showed a high relative in vitro activity against tumour cells from chronic lymphocytic leukaemia and high-grade lymphoma. </p><p>In a phase I trial we determined the maximum tolerated dose (MTD) of CHS 828. Haematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Non-haematological toxicity was mostly of gastrointestinal origin. The recommended phase two dose (RPTD) of CHS 828 was estimated to be 20 mg once daily for five days in cycles of 28 days duration.</p><p>In a phase II trial we investigated the effect of CHS 828 on patients diagnosed with B-CLL. In total 12 patients were enrolled. CHS 828 was found to be well tolerated and the most common haematological toxicity was thrombocytopenia. Non-haematological toxicities were generally mild. Transient decreases in lymphocyte counts could be discerned coinciding with drug dosing, but no sustained clinical responses could be achieved.</p><p>In conclusion, CHS 828 demonstrated marked effects in the preclinical investigations suggesting haematological malignancies as the main target. The clinical phase I study established a safe dose and the subsequent phase II trial in B-CLL patients showed biological effect but with no clinical disease response. </p>

CHS 828 is a cyanoguanidine with anti-tumour properties which has shown promising effects in several preclinical models. This thesis describes both preclinical and clinical studies aiming to investigate disease specific activity, clinical tolerability and efficacy of CHS 828. In paper I we investigated CHS 828 activity in a cell line panel with human myeloma cells, three of these cell-lines were also tested in vivo using a hollow fibre rat-model. In paper II we investigated CHS 828 activity in primary human tumour samples from patients. CHS 828 showed an effect on all tumour cell types tested both the primary human tumour samples and the myeloma cell lines. Notably, CHS 828 showed a high relative in vitro activity against tumour cells from chronic lymphocytic leukaemia and high-grade lymphoma. In a phase I trial we determined the maximum tolerated dose (MTD) of CHS 828. Haematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Non-haematological toxicity was mostly of gastrointestinal origin. The recommended phase two dose (RPTD) of CHS 828 was estimated to be 20 mg once daily for five days in cycles of 28 days duration. In a phase II trial we investigated the effect of CHS 828 on patients diagnosed with B-CLL. In total 12 patients were enrolled. CHS 828 was found to be well tolerated and the most common haematological toxicity was thrombocytopenia. Non-haematological toxicities were generally mild. Transient decreases in lymphocyte counts could be discerned coinciding with drug dosing, but no sustained clinical responses could be achieved. In conclusion, CHS 828 demonstrated marked effects in the preclinical investigations suggesting haematological malignancies as the main target. The clinical phase I study established a safe dose and the subsequent phase II trial in B-CLL patients showed biological effect but with no clinical disease response.

University of Macau / Institute of Chinese Medical Sciences

A thesis submitted to the Faculty of Science, University of the Witwatersrand Johannesburg. In fulfilment of the requirements for the Degree of Doctor of Philosophy. March 2017 / In this PhD thesis, we report for the first time, new methodology for the synthesis of angucycline antibiotic natural products. In particular, for the synthesis of 1,8-dihydroxy-3methyltetraphene-7,12-dione, commonly known as tetrangulol. We also report on the synthesis of 1,10,12-trimethoxy-8-methylbenzo[c]phenanthridine in our quest to synthesise phenanthroviridone from an intermediate product in the synthesis of tetrangulol. The Suzuki-Miyaura coupling reaction between 1,4,5-(trimethoxynaphthalen-2-yl)boronic acid and 2-iodo-3-methoxy-5-methylbenzaldehyde afforded intermediate, 3-methoxy-5methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde. Conversion of this benzaldehyde into the alkyne, 2-(2-ethynyl-6-methoxy-4-methylphenyl)-1,4,5-trimethoxynaphthalene was accomplished utilizing the Corey-Fuchs reaction. Exposure of the derived acetylene to a catalytic platinum(II)-mediated ring closure yielded the required tetracyclic aromatic product, 1,7,8,12-tetramethoxy-3-methyltetraphene which was converted into tetrangulol. Exposure of the related 3-methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde O-phenyl oxime to microwave irradiation in an ionic liquid yielded 1,10,12-trimethoxy-8methylbenzo[c]phenanthridine, instead of the desired natural product phenanthroviridone. We also report on the unexpected synthesis of the benzonaphthopyranone core found in other classes of angucycline antibiotics from oxygen analogs of 2-naphthylbenzyl alcohols when exposed to N-bromosuccinimide. Treatment of (2-(1,4-dimethoxynaphthalen-2yl)phenyl)methanol and related analogues with N-bromosuccinimide under an oxygen atmosphere afforded 12-methoxy-6H-dibenzo[c,h]chromen-6-one, 2-Methoxy-6Hbenzo[c]chromen-6-one and of 6H-benzo[c]chromen-6-one. An investigation into possible mechanisms for this transformation was also conducted. / LG2017