New synthetic methodologies to access 3-benz(o)ylmenadiones and their redox properties at the origin of their antipaludic mode(s) of action.

Le paludisme est une maladie parasitaire tropicale touchant particulièrement les jeunes enfants en Afrique subsaharienne. La résistance aux médicaments antipaludiques s’est développée dans le monde entier depuis près de 50 ans et le besoin de nouveaux composés actifs est urgent. La plasmodione, appartenant à la série des 3-benzylménadiones, est un candidat médicament efficace agissant en interférant avec l’équilibre rédox du parasite. Cependant ses proprietés physico-chimiques sont incompatibles avec un traitement antipaludique efficace par voie orale et son mécanisme d’action est encore mal connu. Durant cette thèse nous avons développé diverses méthodes de synthèse, i) des métabolites postulés : les 3-benzoylménadiones, et ii) des analogues variés de la plasmodione. Les 3-benzoylménadiones ont été obtenues par un nouveau variant de la réaction de Friedel-Crafts clé. Cette réaction a permis également de synthétiser des sondes chimiques (pro-)ABPP pour identifier les sites d’intéractions de ces métabolites avec des enzymes. Une nouvelle voie alternative de synthèse photorédox vers la série 3-benzylménadione a également été développée, permettant d’une part d’obtenir en une seule étape une plus grande variété de ces dérivés fonctionnalisés, mais aussi, grâce son mécanisme original impliquant des cascades rédox, de mieux comprendre la photoréactivité des naphtoquinones. Enfin, des analogues hétéroaromatiques de la plasmodione, avec une solubilité potentielle améliorée, ont été obtenus grâce à un couplage de Suzuki-Miyaura.Malaria is a tropical parasitic disease that particularly affects young children in sub-Saharan Africa. Resistance to antimalarial drugs has been developing worldwide for nearly 50 years and there is an urgent need for new active compounds. Plasmodione, belonging to the 3-benzylmenadione series, is an effective drug candidate acting by interfering with the redox equilibrium of the parasite. However, its physicochemical properties are incompatible with an effective antimalarial treatment per os and its mechanism of action is still poorly understood. During this thesis we have developed various synthetic methods to synthesize i) the postulated metabolites: the 3-benzoylmenadiones, and ii) diverse analogues of plasmodione. The 3-benzoylmenadiones were obtained by a new variant of the key Friedel-Crafts reaction. This reaction also allowed the synthesis of (pro-)ABPP chemical probes to identify the sites of interaction of these metabolites with enzymes. A new alternative photoredox synthesis route to the 3-benzylmenadione series was also developed, allowing on the one hand to obtain in a single step a greater variety of these functionalized derivatives, but also, thanks to its original mechanism involving redox cascades, to better understand the photoreactivity of naphthoquinones. Finally, heteroaromatic analogues of plasmodione, with improved potential solubility, were obtained through a Suzuki-Miyaura coupling

New synthetic methodologies to access 3-benz(o)ylmenadiones and their redox properties at the origin of their antipaludic mode(s) of action.

Le paludisme est une maladie parasitaire tropicale touchant particulièrement les jeunes enfants en Afrique subsaharienne. La résistance aux médicaments antipaludiques s’est développée dans le monde entier depuis près de 50 ans et le besoin de nouveaux composés actifs est urgent. La plasmodione, appartenant à la série des 3-benzylménadiones, est un candidat médicament efficace agissant en interférant avec l’équilibre rédox du parasite. Cependant ses proprietés physico-chimiques sont incompatibles avec un traitement antipaludique efficace par voie orale et son mécanisme d’action est encore mal connu. Durant cette thèse nous avons développé diverses méthodes de synthèse, i) des métabolites postulés : les 3-benzoylménadiones, et ii) des analogues variés de la plasmodione. Les 3-benzoylménadiones ont été obtenues par un nouveau variant de la réaction de Friedel-Crafts clé. Cette réaction a permis également de synthétiser des sondes chimiques (pro-)ABPP pour identifier les sites d’intéractions de ces métabolites avec des enzymes. Une nouvelle voie alternative de synthèse photorédox vers la série 3-benzylménadione a également été développée, permettant d’une part d’obtenir en une seule étape une plus grande variété de ces dérivés fonctionnalisés, mais aussi, grâce son mécanisme original impliquant des cascades rédox, de mieux comprendre la photoréactivité des naphtoquinones. Enfin, des analogues hétéroaromatiques de la plasmodione, avec une solubilité potentielle améliorée, ont été obtenus grâce à un couplage de Suzuki-Miyaura.Malaria is a tropical parasitic disease that particularly affects young children in sub-Saharan Africa. Resistance to antimalarial drugs has been developing worldwide for nearly 50 years and there is an urgent need for new active compounds. Plasmodione, belonging to the 3-benzylmenadione series, is an effective drug candidate acting by interfering with the redox equilibrium of the parasite. However, its physicochemical properties are incompatible with an effective antimalarial treatment per os and its mechanism of action is still poorly understood. During this thesis we have developed various synthetic methods to synthesize i) the postulated metabolites: the 3-benzoylmenadiones, and ii) diverse analogues of plasmodione. The 3-benzoylmenadiones were obtained by a new variant of the key Friedel-Crafts reaction. This reaction also allowed the synthesis of (pro-)ABPP chemical probes to identify the sites of interaction of these metabolites with enzymes. A new alternative photoredox synthesis route to the 3-benzylmenadione series was also developed, allowing on the one hand to obtain in a single step a greater variety of these functionalized derivatives, but also, thanks to its original mechanism involving redox cascades, to better understand the photoreactivity of naphthoquinones. Finally, heteroaromatic analogues of plasmodione, with improved potential solubility, were obtained through a Suzuki-Miyaura coupling

Nouvelles méthodologies de synthèse de 3-benz(o)ylménadiones et propriétés rédox à l'origine de leur(s) mode(s) d'action antipaludique

Malaria is a tropical parasitic disease that particularly affects young children in sub-Saharan Africa. Resistance to antimalarial drugs has been developing worldwide for nearly 50 years and there is an urgent need for new active compounds. Plasmodione, belonging to the 3-benzylmenadione series, is an effective drug candidate acting by interfering with the redox equilibrium of the parasite. However, its physicochemical properties are incompatible with an effective antimalarial treatment per os and its mechanism of action is still poorly understood. During this thesis we have developed various synthetic methods to synthesize i) the postulated metabolites: the 3-benzoylmenadiones, and ii) diverse analogues of plasmodione. The 3-benzoylmenadiones were obtained by a new variant of the key Friedel-Crafts reaction. This reaction also allowed the synthesis of (pro-)ABPP chemical probes to identify the sites of interaction of these metabolites with enzymes. A new alternative photoredox synthesis route to the 3-benzylmenadione series was also developed, allowing on the one hand to obtain in a single step a greater variety of these functionalized derivatives, but also, thanks to its original mechanism involving redox cascades, to better understand the photoreactivity of naphthoquinones. Finally, heteroaromatic analogues of plasmodione, with improved potential solubility, were obtained through a Suzuki-Miyaura coupling.Le paludisme est une maladie parasitaire tropicale touchant particulièrement les jeunes enfants en Afrique subsaharienne. La résistance aux médicaments antipaludiques s’est développée dans le monde entier depuis près de 50 ans et le besoin de nouveaux composés actifs est urgent. La plasmodione, appartenant à la série des 3-benzylménadiones, est un candidat médicament efficace agissant en interférant avec l’équilibre rédox du parasite. Cependant ses proprietés physico-chimiques sont incompatibles avec un traitement antipaludique efficace par voie orale et son mécanisme d’action est encore mal connu. Durant cette thèse nous avons développé diverses méthodes de synthèse, i) des métabolites postulés : les 3-benzoylménadiones, et ii) des analogues variés de la plasmodione. Les 3-benzoylménadiones ont été obtenues par un nouveau variant de la réaction de Friedel-Crafts clé. Cette réaction a permis également de synthétiser des sondes chimiques (pro-)ABPP pour identifier les sites d’intéractions de ces métabolites avec des enzymes. Une nouvelle voie alternative de synthèse photorédox vers la série 3-benzylménadione a également été développée, permettant d’une part d’obtenir en une seule étape une plus grande variété de ces dérivés fonctionnalisés, mais aussi, grâce son mécanisme original impliquant des cascades rédox, de mieux comprendre la photoréactivité des naphtoquinones. Enfin, des analogues hétéroaromatiques de la plasmodione, avec une solubilité potentielle améliorée, ont été obtenus grâce à un couplage de Suzuki-Miyaura

Unprecedented Affinity Labeling of Carbohydrate-Binding Proteins with s -Triazinyl Glycosides

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A Class of Valuable (Pro-)Activity-Based Protein Profiling Probes: Application to the Redox-Active Antiplasmodial Agent, Plasmodione

Plasmodione (PD) is a potent antimalarial redox-active drug acting at low nM range concentrations on different malaria parasite stages. In this study, in order to determine the precise PD protein interactome in parasites, we developed a class of (pro-)activity-based protein profiling probes (ABPP) as precursors of photoreactive benzophenone-like probes based on the skeleton of PD metabolites (PDO) generated in a cascade of redox reactions. Under UV-photoirradiation, we clearly demonstrate that benzylic oxidation of 3-benzylmenadione 11 produces the 3-benzoylmenadione probe 7, allowing investigation of the proof-of-concept of the ABPP strategy with 3-benzoylmenadiones 7−10. The synthesized 3-benzoylmenadiones, probe 7 with an alkyne group or probe 9 with -NO2 in para position of the benzoyl chain, were found to be the most efficient photoreactive and clickable probes. In the presence of various H-donor partners, the UV-irradiation of the photoreactive ABPP probes generates different adducts, the expected “benzophenone-like” adducts (pathway 1) in addition to “benzoxanthone” adducts (via two other pathways, 2 and 3). Using both human and Plasmodium falciparum glutathione reductases, three protein ligand binding sites were identified following photolabeling with probes 7 or 9. The photoreduction of 3-benzoylmenadiones (PDO and probe 9) promoting the formation of both the corresponding benzoxanthone and the derived enone could be replaced by the glutathione reductase-catalyzed reduction step. In particular, the electrophilic character of the benzoxanthone was evidenced by its ability to alkylate heme, as a relevant event supporting the antimalarial mode of action of PD. This work provides a proof-of-principle that (pro-)ABPP probes can generate benzophenone-like metabolites enabling optimized activity-based protein profiling conditions that will be instrumental to analyze the interactome of early lead antiplasmodial 3-benzylmenadiones displaying an original and innovative mode of action

Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands

G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets

Exploring the Dispersion and Electrostatic Components in Arene–Arene Interactions between Ligands and G4 DNA to Develop G4-Ligands

G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene–arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets

Exploring the Dispersion and Electrostatic Components in Arene–Arene Interactions between Ligands and G4 DNA to Develop G4-Ligands

G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene–arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets