The Experts below are selected from a list of 48 Experts worldwide ranked by ideXlab platform
Shinji Oikawa - One of the best experts on this subject based on the ideXlab platform.
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the mechanisms of oxidative dna damage and apoptosis induced by norsalsolinol an endogenous Tetrahydroisoquinoline Derivative associated with parkinson s disease
Journal of Neurochemistry, 2009Co-Authors: Hatasu Kobayashi, Kiyoshi Fukuhara, Saeko Tadaoikawa, Yuki Yada, Yusuke Hiraku, Mariko Murata, Shinji OikawaAbstract:Tetrahydroisoquinoline (TIQ) Derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells.
Hiroyuki Miyachi - One of the best experts on this subject based on the ideXlab platform.
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synthesis of both enantiomers of 1 2 3 4 Tetrahydroisoquinoline Derivative ippam 1 and enantio dependency of its positive allosteric modulation of prostacyclin receptor
Bioorganic & Medicinal Chemistry Letters, 2017Co-Authors: Kohki Yamamoto, Riyo Imamura, Takayoshi Okabe, Toshifumi Suzuki, Tetsuo Nagano, Hiroyuki MiyachiAbstract:We present a practical synthesis of both enantiomers of 1,2,3,4-Tetrahydroisoquinoline Derivative IPPAM-1 (1), which is a positive allosteric modulator (PAM) of prostacyclin receptor (IP) and a candidate for treatment of pulmonary arterial hypertension without the side effects caused by IP agonists. Assay of cAMP production by CHO-K1 cells stably expressing human IP clearly demonstrated that the IPPAM activity resides exclusively on the R-form of 1.
Dufour Fabien - One of the best experts on this subject based on the ideXlab platform.
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Synthesis in the carbazolic series, ellipticine analogues and dihydrocarbazolocarbazoles
2007Co-Authors: Dufour FabienAbstract:L’ellipticine, alcaloïde tétracyclique naturel au squelette 6H-pyrido[4,3-b]carbazole, et certains de ses dérivés possèdent des propriétés antitumorales. L’objectif de ce travail a été, d’une part de trouver une méthode de synthèse de deux types d’intermédiaires précis non décrits à notre connaissance (dérivés du carbazole et de la pyridine), puis de synthétiser des analogues d’ellipticine possédant un cycle saturé supplémentaire, ces modifications structurales pouvant être intéressantes du point de vue de l’activité biologique. Initialement envisagée à partir de dérivés du furane par ouverture du cycle furanique en milieu acide, les dérivés carbazoliques 10-méthyl-1,10-dihydrocyclopenta[a]carbazol-3(2H)-one, 1,2,3,11-tétrahydro-4H-benzo[a]carbazol-4-one, 2,3,4,11-tétrahydro-1H-benzo[a]carbazol-1-one, et 11-méthyl-1,2,3,11-tétrahydro-4H-benzo[a]carbazol-4-one ont finalement été obtenus grâce à la synthèse indolique de Fischer, puis réaction de Friedel-Crafts pour la première molécule et réduction par les métaux dissous, oxydation par la DDQ pour les trois suivantes. Un des dérivés carbazoliques synthétisés nous a fourni par la méthode d’Eloy et Deryckere des analogues de l’ellipticine contenant un cycle saturé supplémentaire à six chaînons, molécules au squelette 1,2,3,12-tétrahydroisoquino[5,4-ab]carbazole, le produit final possédant une chaîne polyaminée, considérée comme utile pour obtenir une activité biologique significative. D’autres systèmes hétérocycliques ont été synthétisés à partir des intermédiaires carbazoliques, notamment des nouveaux dihydrocarbazolocarbazolesEllipticine, a tetracyclic natural alkaloid with the 6H-pyrido[4,3-b]carbazole skeleton and some of its Derivatives display antitumoral properties. The aim of this work was firstly to find a general method to synthesize two types of intermediates not described in the literature to our knowledge (carbazole and pyridine Derivatives), and then to synthesize some ellipticine analogs, which contain an additional saturated cycle, these structural modifications could be interesting regarding to biological activity. The synthesis was initially thought starting from furan Derivatives, and opening of the ring under acidic conditions. 10-Methyl-1,10-dihydrocyclopenta[a]carbazol-3(2H)-one, 1,2,3,11-tetrahydro-4H-benzo[a]carbazol-4-one, 2,3,4,11-tetrahydro-1H-benzo[a]carbazol-1-one, and 11-methyl-1,2,3,11-tetrahydro-4H-benzo[a]carbazol-4-one were eventually obtained by Fischer indole synthesis, followed by Friedel-Crafts reaction for the first product and dissolved metal reduction, DDQ oxidation for the three other molecules. Second hoped intermediates, for instance 5,6,7,8-Tetrahydroisoquinoline Derivative 3-chloro-7,8-dihydro-6H-isoquinolin-5-one, were not obtained. One of the carbazolic Derivatives afforded by the Eloy and Deryckere method ellipticine analogs containing an additional 6-member saturated ring, molecule having a 1,2,3,12-tetrahydroisoquino[5,4-ab]carbazole scaffold. Final product of this synthesis has a polyaminated chain, needed to find a biological activity. Other heterocyclic systems were synthesized from the carbazolic intermediates, like some new dihydrocarbazolocarbazole
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Synthèse en série carbazolique, analogues d'ellipticine, et dihydrocarbazolocarbazoles
2007Co-Authors: Dufour Fabien, Kirsch GilbertAbstract:L ellipticine, alcaloïde tétracyclique naturel au squelette 6H-pyrido[4,3-b]carbazole, et certains de ses dérivés possèdent des propriétés antitumorales. L objectif de ce travail a été, d une part de trouver une méthode de synthèse de deux types d intermédiaires précis non décrits à notre connaissance (dérivés du carbazole et de la pyridine), puis de synthétiser des analogues d ellipticine possédant un cycle saturé supplémentaire, ces modifications structurales pouvant être intéressantes du point de vue de l activité biologique. Initialement envisagée à partir de dérivés du furane par ouverture du cycle furanique en milieu acide, les dérivés carbazoliques 10-méthyl-1,10-dihydrocyclopenta[a]carbazol-3(2H)-one, 1,2,3,11-tétrahydro-4H-benzo[a]carbazol-4-one, 2,3,4,11-tétrahydro-1H-benzo[a]carbazol-1-one, et 11-méthyl-1,2,3,11-tétrahydro-4H-benzo[a]carbazol-4-one ont finalement été obtenus grâce à la synthèse indolique de Fischer, puis réaction de Friedel-Crafts pour la première molécule et réduction par les métaux dissous, oxydation par la DDQ pour les trois suivantes. Un des dérivés carbazoliques synthétisés nous a fourni par la méthode d Eloy et Deryckere des analogues de l ellipticine contenant un cycle saturé supplémentaire à six chaînons, molécules au squelette 1,2,3,12-tétrahydroisoquino[5,4-ab]carbazole, le produit final possédant une chaîne polyaminée, considérée comme utile pour obtenir une activité biologique significative. D autres systèmes hétérocycliques ont été synthétisés à partir des intermédiaires carbazoliques, notamment des nouveaux dihydrocarbazolocarbazolesEllipticine, a tetracyclic natural alkaloid with the 6H-pyrido[4,3-b]carbazole skeleton and some of its Derivatives display antitumoral properties. The aim of this work was firstly to find a general method to synthesize two types of intermediates not described in the literature to our knowledge (carbazole and pyridine Derivatives), and then to synthesize some ellipticine analogs, which contain an additional saturated cycle, these structural modifications could be interesting regarding to biological activity. The synthesis was initially thought starting from furan Derivatives, and opening of the ring under acidic conditions. 10-Methyl-1,10-dihydrocyclopenta[a]carbazol-3(2H)-one, 1,2,3,11-tetrahydro-4H-benzo[a]carbazol-4-one, 2,3,4,11-tetrahydro-1H-benzo[a]carbazol-1-one, and 11-methyl-1,2,3,11-tetrahydro-4H-benzo[a]carbazol-4-one were eventually obtained by Fischer indole synthesis, followed by Friedel-Crafts reaction for the first product and dissolved metal reduction, DDQ oxidation for the three other molecules. Second hoped intermediates, for instance 5,6,7,8-Tetrahydroisoquinoline Derivative 3-chloro-7,8-dihydro-6H-isoquinolin-5-one, were not obtained. One of the carbazolic Derivatives afforded by the Eloy and Deryckere method ellipticine analogs containing an additional 6-member saturated ring, molecule having a 1,2,3,12-tetrahydroisoquino[5,4-ab]carbazole scaffold. Final product of this synthesis has a polyaminated chain, needed to find a biological activity. Other heterocyclic systems were synthesized from the carbazolic intermediates, like some new dihydrocarbazolocarbazolesMETZ-SCD (574632105) / SudocSudocFranceF
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Synthèse en série carbazolique, analogues d'ellipticine, et dihydrocarbazolocarbazoles
HAL CCSD, 2007Co-Authors: Dufour FabienAbstract:Ellipticine, a tetracyclic natural alkaloid with the 6H-pyrido[4,3-b]carbazole skeleton and some of its Derivatives display antitumoral properties. The aim of this work was firstly to find a general method to synthesize two types of intermediates not described in the literature to our knowledge (carbazole and pyridine Derivatives), and then to synthesize some ellipticine analogs, which contain an additional saturated cycle, these structural modifications could be interesting regarding to biological activity. The synthesis was initially thought starting from furan Derivatives, and opening of the ring under acidic conditions. 10-Methyl-1,10-dihydrocyclopenta[a]carbazol-3(2H)-one, 1,2,3,11-tetrahydro-4H-benzo[a]carbazol-4-one, 2,3,4,11-tetrahydro-1H-benzo[a]carbazol-1-one, and 11-methyl-1,2,3,11-tetrahydro-4H-benzo[a]carbazol-4-one were eventually obtained by Fischer indole synthesis, followed by Friedel-Crafts reaction for the first product and dissolved metal reduction, DDQ oxidation for the three other molecules. Second hoped intermediates, for instance 5,6,7,8-Tetrahydroisoquinoline Derivative 3-chloro-7,8-dihydro-6H-isoquinolin-5-one, were not obtained. One of the carbazolic Derivatives afforded by the Eloy and Deryckere method ellipticine analogs containing an additional 6-member saturated ring, molecule having a 1,2,3,12-tetrahydroisoquino[5,4-ab]carbazole scaffold. Final product of this synthesis has a polyaminated chain, needed to find a biological activity. Other heterocyclic systems were synthesized from the carbazolic intermediates, like some new dihydrocarbazolocarbazolesL'ellipticine, alcaloïde tétracyclique naturel au squelette 6H-pyrido[4,3-b]carbazole, et certains de ses dérivés possèdent des propriétés antitumorales. L'objectif de ce travail a été, d'une part de trouver une méthode de synthèse de deux types d?intermédiaires précis non décrits à notre connaissance (dérivés du carbazole et de la pyridine), puis de synthétiser des analogues d'ellipticine possédant un cycle saturé supplémentaire, ces modifications structurales pouvant être intéressantes du point de vue de l?activité biologique. Initialement envisagée à partir de dérivés du furane par ouverture du cycle furanique en milieu acide, les dérivés carbazoliques 10-méthyl-1,10-dihydrocyclopenta[a]carbazol-3(2H)-one, 1,2,3,11-tétrahydro-4H-benzo[a]carbazol-4-one, 2,3,4,11-tétrahydro-1H-benzo[a]carbazol-1-one, et 11-méthyl-1,2,3,11-tétrahydro-4H-benzo[a]carbazol-4-one ont finalement été obtenus grâce à la synthèse indolique de Fischer, puis réaction de Friedel-Crafts pour la première molécule et réduction par les métaux dissous, oxydation par la DDQ pour les trois suivantes. Un des dérivés carbazoliques synthétisés nous a fourni par la méthode d'Eloy et Deryckere des analogues de l'ellipticine contenant un cycle saturé supplémentaire à six chaînons, molécules au squelette 1,2,3,12-tétrahydroisoquino[5,4-ab]carbazole, le produit final possédant une chaîne polyaminée, considérée comme utile pour obtenir une activité biologique significative. D'autres systèmes hétérocycliques ont été synthétisés à partir des intermédiaires carbazoliques, notamment des nouveaux dihydrocarbazolocarbazole
Toshio Honda - One of the best experts on this subject based on the ideXlab platform.
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the first total synthesis of annosqualine by means of oxidative enamide phenol coupling pronounced effect of phenoxide formation on the phenol oxidation mechanism
Tetrahedron Letters, 2006Co-Authors: Hiroki Shigehisa, Jun Takayama, Toshio HondaAbstract:Abstract The first total synthesis of a spiro-isoquinoline alkaloid, (±)-annosqualine, was established by employing an enamide–phenol coupling of a 1-methylene-1,2,3,4-Tetrahydroisoquinoline Derivative with a hypervalent iodine reagent, where the formation of the phenoxide was recognized to be an essential step for the reaction of the phenolic hydroxyl group with the hypervalent iodine reagent leading to the formation of the desired product.
Hatasu Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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the mechanisms of oxidative dna damage and apoptosis induced by norsalsolinol an endogenous Tetrahydroisoquinoline Derivative associated with parkinson s disease
Journal of Neurochemistry, 2009Co-Authors: Hatasu Kobayashi, Kiyoshi Fukuhara, Saeko Tadaoikawa, Yuki Yada, Yusuke Hiraku, Mariko Murata, Shinji OikawaAbstract:Tetrahydroisoquinoline (TIQ) Derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells.