Global food and nutritional insecurities, public health challenges of diet-linked non-communicable chronic diseases (NCDs), and rapid climate change-linked agricultural production challenges are interconnected and require urgent attention. Therefore, to address these complex and interconnected challenges, it is essential to advance robust and resilient strategies based on sustainable agricultural production practices, wider integration of nutritionally-balanced plant-based foods in the diet, improvement of human health-targeted nutritional qualities, post-harvest preservation qualities and food processing optimization. Therefore, food plants that are climate resilient and rich source of human health protective nutritional bioactives, such as sweet potato are ideal dietary targets for advancing global food and nutritional security solutions, while also addressing emerging NCD-linked health challenges. Sweet potatoes are rich source of stress protective phenolic bioactives with dual functional benefits relevant for resilience to climate change and countering diet-linked NCD challenges. However, the phenolic bioactive compounds and associated health protective functionalities of sweet potatoes vary widely between different flesh color and cultivars, due to different pre-harvest production practices, post-harvest storage conditions, and with different food processing strategies. Therefore, the aim of this dissertation was to screen sweet potato cultivars of different flesh color (off-white, orange, purple) and optimizing different food processing strategies based on optimum phenolic bioactive-linked antioxidant, anti-diabetic and anti-hypertensive properties using metabolically-targeted in vitro assay models. Overall, high soluble phenolic-linked antioxidant activity was observed in purple-fleshed cultivar, while high type 2 diabetes relevant anti-hyperglycemic and anti-hypertensive properties were observed in orange and white-fleshed sweet potatoes. Additionally, improvement in stability and retention of phenolic bioactives and associated functionalities were present in bio-transformed sweet potatoes after fermentation with beneficial lactic acid bacteria (LAB). Furthermore, food processing (deep-frying, baking, steaming, and boiling) optimization studies revealed optimum food processing conditions (cooking temperature, cooking time, and sweet potato sample size) based on higher retention of phenolics and associated antioxidant and anti-hyperglycemic functionalities. We also advanced metabolically-driven elicitation strategy based on the conceptual foundation of dual functional benefits of phenolic compounds to improve wound-healing in bruised potato tubers through stimulation of redox-linked pathway (pentose phosphate pathway) regulation associated with stress-protective phenolic biosynthesis and antioxidant enzyme responses.

Ce travail de thèse s’intéresse à la synthèse totale d'alcaloïdes de la famille des Lycorines, produits naturels isolés à partir de plantes des Amaryllidaceae qui possèdent de multiples activités biologiques. Leurs structures sont caractérisées par un squelette commun tétracyclique azoté : le galanthane. L’accès rapide au squelette galanthane a été développé via une étape clé de métathèse tandem cyclisante permettant d’obtenir deux cycles fonctionnalisés en une seule étape. La première partie de ce travail a conduit au développement d’une voie de synthèse asymétrique des (–)-α et (–)-β-lycoranes à partir d’un même intermédiaire, une sulfinylaldimine α-chirale, obtenue par réduction d’un N-sulfinylthioimidate α-chiral grâce à des conditions développées au laboratoire. La seconde partie de ce travail a porté sur la synthèse asymétrique de la (+)-kirkine, nécessitant une révision de la stratégie pour former le cycle B du squelette galanthane de manière précoce dans la synthèse. Nous avons réalisé la première synthèse totale asymétrique de la structure décrite de la (+)-kirkine. L’obtention des lycoranes et de la kirkine prouve la flexibilité ainsi que l'efficacité de la voie de synthèse, en particulier de l'étape clé de métathèse tandem et des N-sulfinylthioimidates comme intermédiaires clés. Cette voie est donc très prometteuse pour accéder à d'autres composés naturels de la famille des Lycorines. / This thesis work focuses on the total synthesis of alkaloids of the Lycorine family, natural products isolated from the plants of Amaryllidaceae, owning many biological properties such as anticancer, antiviral, antimicrobial or anti-inflammatory. Their structure is characterized by a nitrogen-containing tetracyclic galanthan skeleton. A fast access to the galanthan skeleton was developed by a key tandem ring closing metathesis step to obtain two cycles in a single step. The first part of this work concerns the development of an asymmetric synthetic pathway to obtain the (–)-α and (–)-β-lycoranes from a common central intermediate, an α-chiral sulfinylaldimine, obtained by reduction of the corresponding α-chiral sulfinylthioimidate. The second part of this work focuses on the asymmetric synthesis of (+)-kirkine, which required a strategy revision for the formation of the B cycle of the galanthan skeleton earlier in the synthesis. We have succeeded in realising the first asymmetric total synthesis of the described structure for (+)-kirkine. The asymmetric synthesis of lycoranes and kirkine proves the flexibility and efficiency of the synthetic route, in particular of the tandem metathesis step and the N-sulfinylthioimidates as key intermediates. This synthetic pathway is therefore very promising to obtain other natural products of the Lycorine family.

京都大学 / 0048 / 新制・論文博士 / 博士(農学) / 乙第12822号 / 論農博第2795号 / 新制||農||1025(附属図書館) / 学位論文||H26||N4817(農学部図書室) / 31309 / 京都大学農学研究科食品生物科学専攻 / (主査)教授 喜多 恵子, 教授 三上 文三, 教授 栗原 達夫 / 学位規則第4条第2項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21682号 / 医博第4488号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妻木 範行, 教授 大森 孝一, 教授 別所 和久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

No description available.

No description available.

<p>Natural products, along with natural product derivatives, are known to be at the root of the development of many pharmaceuticals, oftentimes showing unique bioactivity against interesting targets. Specifically, natural products containing furans show activity against a variety of diseases including fungal infections, and cancers. It is hypothesized that unknown natural products containing furans could show more potent or other biological activities. However, it is challenging to discover and isolate these small molecules from cell supernatant. The work described herein showcases the development of a molecular probe that can covalently attach to furan moieties via a [4 + 2] Diels-Alder cycloaddition, making them easily identifiable on liquid chromatography mass spectroscopy (LC-MS). The molecular probe, which undergoes this reaction with a variety of furans, was designed with both a UV-tag and a mass tag to enable easy identification. The probe has been tested with a variety of purified furans, including natural products, methylenomycin furan (MMF) hormones, and MMF derivatives. Moreover, work has begun to test the molecular probe in cell supernatants. </p>

The soil bacterium Rhodococcus has a wide array of secondary metabolic pathways such as production of pigments, siderophores, and antibiotics that makes it an organism of interest for the production of novel natural products. Analysis of the genome sequence of Rhodococcus indicates the presence of 24 non-ribosomal peptide synthases and 7 polyketide synthases possibly involved in production of secondary metabolites. The use of a solid agar extraction method to screen soil isolates of Rhodococcus for compounds with inhibitory activity against other bacteria resulted in the discovery of a promising candidate molecule. The Rhodococcus strain KCHXC3, isolated from eastern Tennessee soil, produces a substance that inhibits the growth of several Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumonia and Gram-positive bacteria such as Micrococcus luteus and, Staphylococcus aureus. After bulk extraction of this compound with ethyl acetate from agar plates, the material was partially purified through different chromatography processes.

Bioactive compounds, such as curcumin, lutein, coenzyme Q10, β-carotene, cholecalciferol, astaxanthin, and β-sitosterol, have antioxidant and anti-inflammatory properties that promote health, but their low solubility, fast metabolism, and degradation have made it difficult to fully harness their potential. Encapsulation techniques, such as nano and microencapsulation using food-based biopolymers, have been employed to address these challenges. However, research efforts in protein-based delivery have mainly focused on encapsulation without considering structural, physicochemical, and matrix compatibility, which is tedious, unsustainable, and not cost-effective. Hence, this thesis reports the structural basis of guest-host interaction in the gastrointestinal delivery of lipophilic bioactive compounds using protein-based vehicles. This research employed fluorescence quenching techniques to estimate the influence of protein modification, fractionation and ionic strength on the nature and strength of interactions between protein and bioactive compounds. Morphological examination was carried out with transmission electron microscopy, confocal and widefield fluorescence microscopy whereas the sizes of the nano and micro-complexes was measured with dynamic light scattering techniques. Thermal stability was measured with differential scanning calorimetry and functional group characterization done with Fourier Transform infrared spectroscopy. Encapsulation efficiency was estimated by UV-Visible spectroscopy whereas in vitro bioactive compound release study was carried out in simulated salivary, gastric and intestinal fluids. Cytotoxicity assessment was estimated by calcein leakage assay. The study showed that protein modification affects the strength of protein-curcumin interaction and encapsulation efficiency. Pea protein succinylation increased electrostatic interaction with chitosan but decreased protein-curcumin interaction. Pea glutelin, albumin and globulin fractions showed different binding strengths with curcumin and the protein hydrophobicity and encapsulation efficiency correlated positively with the binding strength. The study also investigated the impact of bioactive compound lipophilicity and physiological ionic strength on the interaction between protein and bioactive compound. Lipophilicity influenced the strength of protein-bioactive compound interaction, while ionic strength changed the mode of interaction from static to static-dynamic quenching. The morphology of the nano and micro complexes formed with protein varied depending on the nature of encapsulated bioactive compound. Finally, bio-nano interaction involving giant unilamellar vesicles and curcumin-loaded pea protein of various surface functionalities as model biomembrane and nanoparticles respectively, was investigated. The result showed that while the protein/chitosan shell stabilizes bioactive compounds from degradation, the bioactive compound modulates their interaction with biomembrane. Overall, this work has demonstrated that for a rational design of protein-based nano/micro-encapsulation system, it is essential to consider the influence of the structural and physicochemical properties of proteins and bioactive compounds, stabilizing intermolecular forces, ionic strength of the environment, lipophilicity of the bioactive compounds, mechanism of release and modulation of cytotoxicity by bioactive compound. For instance, in high ionic strength solution, the stoichiometric ratio between protein carrier and bioactive compounds influences the stability of the complex. Balancing the intermolecular forces in the shell and core of bilayer complexes is essential for the stability of nanocomplexes and the presence of bioactive compound stabilizes the macromolecular carrier to minimal biomembrane disruption.