A general catalyzed direct C−H functionalization of s‐tetrazines is reported. Under mild reaction... more A general catalyzed direct C−H functionalization of s‐tetrazines is reported. Under mild reaction conditions, N‐directed ortho‐C−H activation of tetrazines allows the introduction of various functional groups, thus forming carbon–heteroatom bonds: C−X (X=I, Br, Cl) and C−O. Based on this methodology, we developed electrophilic mono‐ and poly‐ortho‐fluorination of tetrazines. Microwave irradiation was optimized to afford fluorinated s‐aryltetrazines, with satisfactory selectivity, within only ten minutes. This work provides an efficient and practical entry for further accessing highly substituted tetrazine derivatives (iodo, bromo, chloro, fluoro, and acetate precursors). It gives access to ortho‐functionalized aryltetrazines which are difficult to obtain by classical Pinner‐like syntheses.
[structure: see text] Bromoacetamidoporphyrin is a convenient synthon for the attachment of dista... more [structure: see text] Bromoacetamidoporphyrin is a convenient synthon for the attachment of distal superstructures at room temperature in good yields. New models are presented that contain a tris-imidazole distal ligand set bound to the porphyrin in either a binary or trinary fashion. More importantly, one distal imidazole is cross-linked to a phenol mimicking Tyr(244), making this model the closest structural analogue yet reported of the metal free cytochrome c oxidase (CcO) active site.
Proceedings of the National Academy of Sciences, 2019
Significance The electronic structure of the heme oxy-iron center in oxyhemoglobin and oxymyoglob... more Significance The electronic structure of the heme oxy-iron center in oxyhemoglobin and oxymyoglobin has been the subject of debate for decades. Various experimental and computational methods have been used to study this system, leading to conflicting conclusions. This study uses X-ray spectroscopy to directly probe the iron center in the highly delocalized oxyhemoglobin and its model compound to define the electronic structure and understand the differences between the protein and the model. This study settles a longstanding debate in bioinorganic chemistry and provides insight into heme iron–oxygen binding, the key first step in many biocatalytic processes.
Proceedings of the National Academy of Sciences, 2012
Platelets are important mediators of blood coagulation that lack nuclei, but contain mitochondria... more Platelets are important mediators of blood coagulation that lack nuclei, but contain mitochondria. Although the presence of mitochondria in platelets has long been recognized, platelet mitochondrial function remains largely unaddressed. On the basis of a small amount of literature that suggests platelet mitochondria are functional, we hypothesized that the inhibition of platelet mitochondria disrupts platelet function and platelet-activated blood coagulation. To test this hypothesis, members of the tetrazole, thiazole, and 1,2,3-triazole families of small molecule heterocycles were screened for the ability to inhibit isolated mitochondrial respiration and coagulation of whole blood. The families of heterocycles screened were chosen on the basis of the ability of the heterocycle family to inhibit a biomimetic model of cytochrome c oxidase (CcO). The strength of mitochondrial inhibition correlates with each compound's ability to deter platelet stimulation and platelet-activated bl...
A general catalyzed direct C-H functionalization of s-tetrazines is reported. Under mild reaction... more A general catalyzed direct C-H functionalization of s-tetrazines is reported. Under mild reaction conditions, N-directed ortho-C-H activation of tetrazines allows the introduction of various functional groups, thus forming carbon-heteroatom bonds: C-X (X=I, Br, Cl) and C-O. Based on this methodology, we developed electrophilic mono- and poly-ortho-fluorination of tetrazines. Microwave irradiation was optimized to afford fluorinated s-aryltetrazines, with satisfactory selectivity, within only ten minutes. This work provides an efficient and practical entry for further accessing highly substituted tetrazine derivatives (iodo, bromo, chloro, fluoro, and acetate precursors). It gives access to ortho-functionalized aryltetrazines which are difficult to obtain by classical Pinner-like syntheses.
La phototherapie dynamique (pdt) est une alternative originale et prometteuse a la chimiotherapie... more La phototherapie dynamique (pdt) est une alternative originale et prometteuse a la chimiotherapie anticancereuse. Le potentiel anticancereux de cette technique repose sur la capacite de certaines molecules photosensibilisatrices a s'incorporer preferentiellement dans les cellules tumorales. L'irradiation de la tumeur par la lumiere de longueur d'onde appropriee induit l'activation du photosensibilisateur qui, ainsi excite, reagit avec les molecules de son environnement et genere des especes cytotoxiques. L'amelioration de cette activite et de la selectivite du ciblage des cellules tumorales necessite la synthese et l'experimentation de nouvelles molecules. C'est dans ce cadre que s'inscrit cette these consacree dans une premiere partie a la synthese de nouvelles hexadecachlorophtalocyanines metallees (al, co, si, zn). Plusieurs methodes ont ete mises en oeuvre et comparees : condensation d'anhydride tetrachlorophtalique et d'uree en presence d'un sel du metal, tetramerisation on pot du tetrachlorophtalonitrile suivie d'une insertion du metal dans le macrocycle. Dans certains cas l'hexadecachlorophtalocyanine de di lithium a d'abord ete synthetisee et le lithium a ete ensuite echange par un autre metal. Les rendements sont de 68 a 80%. L'effet de blindage du macrocycle a par ailleurs permis de preciser, en rmn du proton, l'attribution des signaux des ligands. Une autre serie de phtalocyanines d'aluminium et de silicium, non chlorees, comportant un ou deux ligands lipophiles a ete preparee par couplage du ligand et du metal. Les groupes octyloxy, cholesteryloxy, tri-n-hexylsiloxy et diphenylcholesteryloxysiloxy ont pu etre greffes avec des rendements compris entre 8 et 80%. La deuxieme partie de ce travail est consacree a la determination de l'activite photodynamique des phtalocyanines synthetisees envers plusieurs lignees de melanocytes malins humains : m6, skmel-2, skmel-5, a431 et hbl. Les photosensibilisateurs ont ete utilises en solution ou dans des micelles et des liposomes. Ces systemes ont ete compares et optimises. Si l'hexadecachloration n'apporte pas d'accroissement notable de la phototoxicite, la presence d'un ou de deux ligands hydrophobes exalte l'activite photocytotoxique. Celle-ci augmente avec l'encombrement sterique du ligand mais semble peu dependre de la nature du metal insere dans le macrocycle.
A general catalyzed direct C−H functionalization of s‐tetrazines is reported. Under mild reaction... more A general catalyzed direct C−H functionalization of s‐tetrazines is reported. Under mild reaction conditions, N‐directed ortho‐C−H activation of tetrazines allows the introduction of various functional groups, thus forming carbon–heteroatom bonds: C−X (X=I, Br, Cl) and C−O. Based on this methodology, we developed electrophilic mono‐ and poly‐ortho‐fluorination of tetrazines. Microwave irradiation was optimized to afford fluorinated s‐aryltetrazines, with satisfactory selectivity, within only ten minutes. This work provides an efficient and practical entry for further accessing highly substituted tetrazine derivatives (iodo, bromo, chloro, fluoro, and acetate precursors). It gives access to ortho‐functionalized aryltetrazines which are difficult to obtain by classical Pinner‐like syntheses.
[structure: see text] Bromoacetamidoporphyrin is a convenient synthon for the attachment of dista... more [structure: see text] Bromoacetamidoporphyrin is a convenient synthon for the attachment of distal superstructures at room temperature in good yields. New models are presented that contain a tris-imidazole distal ligand set bound to the porphyrin in either a binary or trinary fashion. More importantly, one distal imidazole is cross-linked to a phenol mimicking Tyr(244), making this model the closest structural analogue yet reported of the metal free cytochrome c oxidase (CcO) active site.
Proceedings of the National Academy of Sciences, 2019
Significance The electronic structure of the heme oxy-iron center in oxyhemoglobin and oxymyoglob... more Significance The electronic structure of the heme oxy-iron center in oxyhemoglobin and oxymyoglobin has been the subject of debate for decades. Various experimental and computational methods have been used to study this system, leading to conflicting conclusions. This study uses X-ray spectroscopy to directly probe the iron center in the highly delocalized oxyhemoglobin and its model compound to define the electronic structure and understand the differences between the protein and the model. This study settles a longstanding debate in bioinorganic chemistry and provides insight into heme iron–oxygen binding, the key first step in many biocatalytic processes.
Proceedings of the National Academy of Sciences, 2012
Platelets are important mediators of blood coagulation that lack nuclei, but contain mitochondria... more Platelets are important mediators of blood coagulation that lack nuclei, but contain mitochondria. Although the presence of mitochondria in platelets has long been recognized, platelet mitochondrial function remains largely unaddressed. On the basis of a small amount of literature that suggests platelet mitochondria are functional, we hypothesized that the inhibition of platelet mitochondria disrupts platelet function and platelet-activated blood coagulation. To test this hypothesis, members of the tetrazole, thiazole, and 1,2,3-triazole families of small molecule heterocycles were screened for the ability to inhibit isolated mitochondrial respiration and coagulation of whole blood. The families of heterocycles screened were chosen on the basis of the ability of the heterocycle family to inhibit a biomimetic model of cytochrome c oxidase (CcO). The strength of mitochondrial inhibition correlates with each compound's ability to deter platelet stimulation and platelet-activated bl...
A general catalyzed direct C-H functionalization of s-tetrazines is reported. Under mild reaction... more A general catalyzed direct C-H functionalization of s-tetrazines is reported. Under mild reaction conditions, N-directed ortho-C-H activation of tetrazines allows the introduction of various functional groups, thus forming carbon-heteroatom bonds: C-X (X=I, Br, Cl) and C-O. Based on this methodology, we developed electrophilic mono- and poly-ortho-fluorination of tetrazines. Microwave irradiation was optimized to afford fluorinated s-aryltetrazines, with satisfactory selectivity, within only ten minutes. This work provides an efficient and practical entry for further accessing highly substituted tetrazine derivatives (iodo, bromo, chloro, fluoro, and acetate precursors). It gives access to ortho-functionalized aryltetrazines which are difficult to obtain by classical Pinner-like syntheses.
La phototherapie dynamique (pdt) est une alternative originale et prometteuse a la chimiotherapie... more La phototherapie dynamique (pdt) est une alternative originale et prometteuse a la chimiotherapie anticancereuse. Le potentiel anticancereux de cette technique repose sur la capacite de certaines molecules photosensibilisatrices a s'incorporer preferentiellement dans les cellules tumorales. L'irradiation de la tumeur par la lumiere de longueur d'onde appropriee induit l'activation du photosensibilisateur qui, ainsi excite, reagit avec les molecules de son environnement et genere des especes cytotoxiques. L'amelioration de cette activite et de la selectivite du ciblage des cellules tumorales necessite la synthese et l'experimentation de nouvelles molecules. C'est dans ce cadre que s'inscrit cette these consacree dans une premiere partie a la synthese de nouvelles hexadecachlorophtalocyanines metallees (al, co, si, zn). Plusieurs methodes ont ete mises en oeuvre et comparees : condensation d'anhydride tetrachlorophtalique et d'uree en presence d'un sel du metal, tetramerisation on pot du tetrachlorophtalonitrile suivie d'une insertion du metal dans le macrocycle. Dans certains cas l'hexadecachlorophtalocyanine de di lithium a d'abord ete synthetisee et le lithium a ete ensuite echange par un autre metal. Les rendements sont de 68 a 80%. L'effet de blindage du macrocycle a par ailleurs permis de preciser, en rmn du proton, l'attribution des signaux des ligands. Une autre serie de phtalocyanines d'aluminium et de silicium, non chlorees, comportant un ou deux ligands lipophiles a ete preparee par couplage du ligand et du metal. Les groupes octyloxy, cholesteryloxy, tri-n-hexylsiloxy et diphenylcholesteryloxysiloxy ont pu etre greffes avec des rendements compris entre 8 et 80%. La deuxieme partie de ce travail est consacree a la determination de l'activite photodynamique des phtalocyanines synthetisees envers plusieurs lignees de melanocytes malins humains : m6, skmel-2, skmel-5, a431 et hbl. Les photosensibilisateurs ont ete utilises en solution ou dans des micelles et des liposomes. Ces systemes ont ete compares et optimises. Si l'hexadecachloration n'apporte pas d'accroissement notable de la phototoxicite, la presence d'un ou de deux ligands hydrophobes exalte l'activite photocytotoxique. Celle-ci augmente avec l'encombrement sterique du ligand mais semble peu dependre de la nature du metal insere dans le macrocycle.
Uploads
Papers by Richard A. Decréau