Lo más importante de nuestro proyecto es la propuesta de valor que ofrece Qatiy; así como la cobertura que brinda a cierto sector del mercado que no se encontraba satisfecho o no contaba con alternativas que cumplieran con sus necesidades. Por ello, es importante resaltar la validación del modelo de negocio; pues, si bien la idea puede ser buena, no necesariamente cumple con las expectativas del consumidor. Por esta razón nuestro producto tuvo que ser evaluado minuciosamente para determinar la viabilidad del consumo para su posterior venta. Otro aspecto determinante se basa en el beneficio que nos brinda en términos financieros; es decir, la alta rentabilidad que podemos obtener tras la puesta en marcha de nuestra empresa. El mercado aún se encuentra en desarrollo y los consumidores cada vez tienen nuevos hábitos y concientización de consumo de productos saludables, lo que significan grandes oportunidades para su explotación. Finalmente, hay que destacar que Qatiy incentiva el consumo de productos hecho a base de alimentos saludables que favorece al bienestar del consumidor, ya que se producen con insumos naturales y sin ningún tipo de preservantes, lo cual es un aporte importante de responsabilidad social por parte de nuestra empresa. / The main thing about our project is the value proposition offered by Qatiy; as well as the coverage it provides to a certain sector of the market that was not satisfied or did not have alternatives meeting their needs. Therefore, it is important to highlight; since, while the idea may be good, it does not necessarily meet consumer expectations. For this reason our product had to be thoroughly evaluated to determine the viability of consumption for subsequent sale. Another determining aspect is based on the benefit it gives us in financial terms; that is the high profitability that we can obtain after the start-up of our company. The market is still in development and consumers are acquiring increasingly new habits and are becoming aware of the benefits of healthy products consumption which means big opportunities for exploitation. Finally, it should be noted that Qatiy encourages the consumption of products made from healthy food that favor the well-being of the consumer, since they are produced with natural supplies and without any preservatives; which is an important contribution of social responsibility by our company. / Trabajo de investigación

Philosophiae Doctor - PhD / Searsia is the more recent name for the genus (Rhus) that contains over 250 individual species of flowering plants in the family Anacardiaceae. Research conducted on Searsia extracts to date indicates a promising potential for this plant group to provide renewable bioproducts with the following reported desirable bioactivities; antimicrobial, antifungal, antiviral, antimalarial, antioxidant, antifibrogenic, anti-inflammatory, antimutagenic, antithrombin, antitumorigenic, cytotoxic, hypoglycaemic, and leukopenic (Rayne and Mazza, 2007, Salimi et al., 2015). Searsia glauca, Searsia lucida and Searsia laevigata were selected for this study. The aim of this study was to isolate, elucidate and evaluate the biological activity of natural products occurring in the plants selected.

Les leustroducsines sont des molécules naturelles issues de la bactérie Streptomyces Platensis. Elles ont montré des activités antifongiques, antibactériennes et antitumorales, les rendant intéressantes pour des études thérapeutiques. Notre équipe s’intéresse à la synthèse de ces composés et notre analyse rétrosynthétique montre que les leustroducsines peuvent s’obtenir par couplage entre trois fragments : un fragment lactone, un fragment dérivé du cyclohexane et un fragment central de type dihydrooxazinone. Nous proposons également une synthèse flexible puisque les trois fragments peuvent être couplés dans différents ordres et la coupure de la liaison N-O peut se faire avant ou après l’addition du fragment lactone. Ceci offre donc de nombreuses solutions de repli. La synthèse de la dihydrooxazinone passe par une réaction de nitroso Diels-Alder régio- et stéréosélective. Nous avons envisagé deux groupements précurseurs de cétone : un bromure de vinyle ou un phosphate d’énol. Dans le premier cas, nous n’avons pas réussi à obtenir la cétone contrairement au deuxième cas, où nous sommes parvenus à former la dihydrooxazinone. La stéréosélectivité a été contrôlée (86 % ee) lors de la réaction de nitroso Diels-Alder par l’emploi du réactif de Wightman, un dérivé nitroso chiral. Quant au fragment lactone, les deux centres asymétriques ont été introduits de manière originale par une cycloaddition [2+2] entre un cétène et un aldéhyde en présence du catalyseur de Nelson chiral. L’ouverture du cycloadduit par de l’acétate de t-butyle suivi d’une lactonisation et déshydratation en milieu acide conduit au fragment lactone avec 90 % ee. Le couplage entre les deux fragments a été réalisé après transformation préalable du fragment lactone en dérivé de lithium avec 46 % de rendement. La réaction de coupure de la liaison N-O est actuellement à l’étude. / Leustroducsins are natural products produced by bacteria called Streptomyces Platensis. They have shown antifungal, antibacterial as well as antitumoral activities, which make them interesting for therapeutic studies.Our team is interested in the synthesis of these compounds and our retrosynthetic analysis shows that leustroducsins can be obtain by a coupling between three fragments: a lactone fragment, a cyclohexane moiety and a dihydrooxazinone type central fragment. We also suggest a flexible synthesis since we can couple the three fragments in different orders and cleavage of the N-O bond can be achieved before or after addition of the lactone fragment. Hence we have many alternative solutions.The dihydrooxazinone is obtained by a regio- and stereoselective nitroso Diels-Alder reaction. We thought of two ketone precursors: vinyl bromide or enol phosphate. In the first case, we did not succeed in forming the ketone contrary to the second case, in which we obtained the dihydrooxazinone. Stereoselectivity was controlled (86 % ee) during nitroso Diels-Alder reaction thanks to the Wightman’s reagent, a chiral nitroso compound. Regarding the lactone fragment, the two stereocenters were introduced via an original [2+2] cycloaddition between a ketene and an aldehyde in the presence of the chiral Nelson’s catalyst. Opening of the cycloadduct by t-butyl acetate followed by lactonisation and dehydration in acidic conditions leads to the lactone fragment with 90 % ee.Coupling of the two fragments was performed after a prior change of the lactone fragment into a lithium derivative with 46 % yield. We are now studying the cleavage of the N-O bond.

>Magister Scientiae - MSc / In modern society, diversity of marine macroalgae has become an inspiration for pharmaceutical companies and researchers because of their numerous health benefits, and a great deal of interest has developed towards the isolation of bioactive compounds to identify novel marine natural products that could eventually be developed into therapeutics or pharmaceutical products. Furthermore, marine macroalgae are valuable source of structurally diverse metabolites with scientifically proven reports. The search continues as there are many natural bioactive compounds that are in the womb of the ocean which are still a mystery. Thus, the present study investigates the natural products from green seaweed Ulva capensis.

Philosophiae Doctor - PhD / Marine organisms including algae and bacteria are known to produce chemically diverse secondary metabolites for survival purposes in the marine environment. Scientists have identified some of these natural products as therapeutic agents including some antibiotics. Given the increase in the resistance of pathogenic microorganisms especially methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis to commonly prescribed antibiotics, researchers have turned towards exploiting marine natural products for new antibacterial compounds. Due to the proven success of finding bioactive compounds in the marine environment this study therefore aims to discover lead compounds against MRSA and Mycobacterium tuberculosis from two marine sources, the marine algae and the bacteria associated with marine invertebrates referred to as bacterial isolates. / 2024

>Magister Scientiae - MSc / Research on natural products and medicinal plants has been conducted more with each passing year due to the great interest in isolating bioactive compounds and secondary metabolites from natural products such as plants, fungi, and many other naturally occurring products. To our knowledge, the Uromycladium tepperianum MacAlpine fungus has not been studied in depth before thus, its organic characterization was unknown, but related species have been studied, and these have shown compounds that may be used as medicine and as health benefits. Crude and macerated extracts of the Uromycladium tepperianum fungus have been fractionized using various chromatographic techniques such as solvent-solvent extraction followed by dry column chromatography to achieve the required separations. Thirty-nine compounds have been isolated from the hexane(n-hex) extract, Ethylacetate (EtOAc) extract, and n-butanol (BuOH) extract, and they belong to the following groups, steroids, terpenoids, amino-acids, flavonoids, alkaloids, phenolics, fatty-acids, flavones, and others.

Rhodococcus bacteria have many secondary metabolic pathways that may produce novel natural products. The bacterium Rhodococcus strain KCHXC3 was isolated from a soil sample collected near Kingsport, Tennessee and was found to produce an inhibitory compound active against a broad array of bacterial species, including the Gram negative pathogen Shigella sonnei. The aim of this research is to extract and purify the compound for future structure elucidation. A mixture of compounds from 3 month old agar plates inoculated with strain KCHXC3 was extracted using ethyl acetate. The crude extract was then partially purified utilizing a Sephadex LH-20 column, followed by an analytical NH2 HPLC column. This purification resulted in a dried crystalline-like active compound that is white in color and needle-like in shape. Structural studies such as NMR and GC-MS revealed the presence of aromatic rings in the active compound that appears to be built with amino acids.

Marineosins A and B are two spiroaminal-ring containing tripyrrole compounds isolated from the marine actinomycete, Streptomyces CNQ-617, and were found to possess potent and selective cytotoxic activity against leukemia and melanoma. Marineosins belong to the prodiginines class of natural products, examples of which are undecylprodiginine and streptorubin B. Unlike marineosins, prodiginines structures are characterized by the presence of fully conjugated tripyrrole nucleus linked to an alkyl chain (that lacks any oxygen). Cyclic prodiginines arise from an oxidative cyclization of the alkyl chain onto the tripyrrole, a step catalyzed by Rieske-oxygenase like enzymes such as RedG. The biosynthesis of prodiginines is directed via the red gene cluster. The unique structural differences between marineosin and other prodiginines spurred the proposal of a number of hypotheses for its biosynthesis, none of which have been experimentally tested. A red gene cluster homolog which has only one extra dehydratase-encoding gene; marA has been identified from the genomic library of Streptomyces CNQ-617, and the identified cluster was proposed to direct the biosynthesis of marineosin. In this study, the identified putative gene cluster was expressed in the heterologous host, S. venezuelae, and marineosin production in the new strain; JND2 was confirmed via LC/MS and 1H-NMR. The new engineered strain also produces a myriad of marineosin related shunt metabolites and pathway intermediates. This study hence presents the first identified gene cluster proved to direct the biosynthesis of marineosin; the mar gene cluster and proves that the cloned cluster encodes most, if not all the enzymes required to direct the biosynthesis of marineosin. Deletion of the Rieske-oxygenase encoding gene; marG (a RedG homolog) from the mar gene cluster led to the accumulation of 2-hydroxyundecylprodiginine; G410 with an m/z 410.28 and molecular formula C25H35O2N3. This data proves that MarG is not responsible for the introduction of the spiromaminal ring oxygen on the alkyl chain, but is required for catalyzing macrocyclic ring formation between C-8 and C-9 of G410. Undecylprodiginine production in marG deletion mutant was not observed which indicates that undecylprodiginine is likely not an intermediate along the pathway for marineosin biosynthesis, and indicates that the spiroaminal ring oxygen is introduced early in the pathway, possibly due to the incorporation of a 3-hydroxy-butyric acid starter unit. Deletion of the dehydratase-encoding gene; marA, from the mar gene cluster led to the accumulation of compounds JN408 and JN422 with m/z 408.26 and 422.24 and molecular formulae C25H33O2N3, and C25H31O3N3, respectively. Purification and structure elucidation of JN408 proves it to be an oxidized marineosin analog which has fully aromatic tripyrrole rings while; purification and structure elucidation of JN422 proves it to be a 9-keto-JN408 derivative. Both JN408 and JN422 compounds have a spiroaminal ring which indicates that MarA does not catalyze spiroaminal ring formation but catalyzes the reduction of pyrrole ring B of JN408 to yield marineosin. Therefore, we are proposing that MarA acts as a dehydrogenase, rather than a dehydratase. We are proposing that the intramolecular spiroaminal ring formation is catalyzed by either MarG or occurs non-enzymatically. JN422 is a shunt metabolite produced due to promiscuous activity of either MarG or an unidentified oxidase in the mar cluster, possibly MarT. From the data generated in this study, we present the first experimentally supported pathway for the biosynthesis of marineosin and the opportunity to generate novel compounds with potentially useful biological activities.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第19673号 / 薬科博第61号 / 新制||薬科||7(附属図書館) / 32709 / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 馬見塚 拓, 教授 掛谷 秀昭, 教授 緒方 博之 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

No description available.