Actinobacteria are well known for the production of bioactive natural products, many of which have applications in the fields of human, animal and plant health. Subject of this thesis are the... Show moreActinobacteria are well known for the production of bioactive natural products, many of which have applications in the fields of human, animal and plant health. Subject of this thesis are the anthracyclines, glycosylated aromatic polyketides with potent anticancer activity. Despite remarkable efficacy against acute leukaemia and various solid tumours, their application is limited by severe side effects, such as cardiotoxicity, therapy-related tumours and infertility.Recent insights into the mode-of-action of anthracyclines have prompted renewed interest into this important class of anticancer compounds. One of the most promising compounds is N,N-dimethyldoxorubicin, which exerts significantly reduced side effects. To date, DMdoxo has not been isolated from natural sources, but biosynthesis would be an attractive option for scaling up production of this promising compound.For this reason, we aimed to engineer the Doxo biosynthetic pathway in S. peucetius for the production of biosynthetic N,N-dimethylated anthracyclines. The challenges that we encountered instigated the study of anthracycline resistance mechanisms in Streptomyces, and potential applications of detoxified anthracyclines as antibiotics. Finally, to facilitate future screening and strain engineering efforts of Streptomyces producer strains, we developed a workflow for integrated quantitative proteomics and metabolomics from small-scale Streptomyces cultures Show less
The world continues to be plagued by numerous diseases and health complications. Unfortunately, current drug discovery efforts are lagging behind compared to the pace of emergence of new diseases... Show moreThe world continues to be plagued by numerous diseases and health complications. Unfortunately, current drug discovery efforts are lagging behind compared to the pace of emergence of new diseases or the development of resistance to current therapies. Medicinal plants especially for people in developing countries are sometimes the only remedies available for the prevention and treatment of diseases. Modern science has also come to recognize the importance of medicinal plants in drug discovery and development given the contributions that this sector has made to drug discovery. As such, several pharmacognostic/natural products chemistry techniques have been developed to aid research on the medicinal properties of plants. The application of these techniques is very useful in two main areas in that they facilitate the validation of the medicinal properties of folk remedies and in the discovery of new remedies from natural products. This thesis focused on the evaluation of the medicinal properties of Vernonia guineensis Benth. (Asteraceae), which is commonly called Ginseng in Cameroon. The species was found to possess antimicrobial, antiplasmodial, antiproliferative/anticancer and anthelmintic effects. Results obtained and reported in this thesis will form a useful foundation for further research into the medicinal potential of this plant Show less
The research described in this Ph.D. Thesis has been devoted to the design and development of polynuclear polypyridyl ruthenium and ruthenium-platinum complexes in search of new anticancer agents.... Show moreThe research described in this Ph.D. Thesis has been devoted to the design and development of polynuclear polypyridyl ruthenium and ruthenium-platinum complexes in search of new anticancer agents. A variety of polynuclear ruthenium and ruthenium-platinum complexes has been synthesized with a long and flexible linker. The complexes are characterized and have been studied for anticancer activity. The ruthenium unit of the dinuclear complexes varies in molecular structure, which may result in different interactions with DNA, the target of anticancer platinum and ruthenium antitumor compounds. The monofunctional ruthenium unit coordinates to the DNA-model base 9-ethylguanine. Variable temperature 1H NMR experiments prove that the base is hindered in its free rotation at room temperature. The crystal structure of a dinuclear ruthenium-platinum complex shows that the platinum unit is capable of intercalation and coordination (in)to DNA. Trinuclear and tetranuclear ruthenium and ruthenium-platinum complexes show higher activity than the dinuclear derivatives. A tetranuclear ruthenium complex displays interesting biological features. Human ovarian cisplatin sensitive carcinoma cells adhere together and form clots upon incubation of the complex. The effect possibly indicates antimetastatic activity. Dinuclear and trinuclear ruthenium-platinum complexes of short and semi-rigid linkers do not show significant activity against different cancer cell lines. Show less
