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Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease
Hroch, Lukáš ; Musílek, Kamil (advisor) ; Farsa, Oldřich (referee) ; Zimčík, Petr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Lukáš Hroch Supervisor assoc. prof. PharmDr. Kamil Musílek, Ph.D. Title of Doctoral Thesis Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease There were about 50 million people living with dementia in 2015. It is expected that number of people living with dementia will reach 130 million by the year of 2050. Alzheimer's disease (AD) is one of the most common causes of dementia and it is estimated to account for about 60 80% of overall cases. Current symptomatic treatment only alleviates symptoms and delays progression of the disease. However, there is no effective treatment, which would address the underlying cause of AD. The extracellular depositions of insoluble amyloid beta peptide (Aβ) were thought to be a causative factor and main target for a long time. Yet, targeted treatment towards the reduction of extracellular Aβ depositions failed to show expected therapeutic merit. Later on, it has been shown that development of AD starts much earlier than any Aβ plaques or symptoms could be observed. With growing evidence of soluble Aβ in intracellular regions, main attention moved to investigations of Aβ within the cells. Aβ...
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Preparation of 3,5,5-Trisubstituted Hydantoins From Activated Cbz-Aminomalonic Acids
Hroch, Lukáš ; Doležal, Martin (advisor) ; Zimčík, Petr (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Supervisor: Prof. Dr. Michael Gütschow Candidate: Lukáš Hroch Title of diploma thesis: Preparation of 3,5,5-Trisubstituted Hydantoins From Activated Cbz-Aminomalonic Acids Hydantoins are of notable importance for drug discovery. Their utilization arises from their scaffold, which offers three distinct positions for possible substitution with a wide range of residues. Accordingly, they can act as biologically active compounds in different ways. The aim of the work was to continue with the project started by M. Hrušková. The unexpected formation of 5-ethyl-3-phenyl-5-(phenylcarbamoyl) hydantoin encouraged the efforts to more deeply explore the potential of the reaction by preparing more of 3,5,5-trisubstituted hydantoins. Preparation of Cbz-aminomalonic acids started with the protection of the amino group of diethyl 2-aminomalonate hydrochloride. Diethyl 2-(benzyloxycarbonylamino) malonate 4 was alkylated and consequently diethyl 2-alkyl-2- (benzyloxycarbonylamino)malonates 5 were saponified to afford 2-alkyl-2- (benzyloxycarbonylamino)malonic acids 6. Then, the activation with oxalyl chloride and treatment with primary aromatic amines followed. 3,5-Disubstituted...
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Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease
Hroch, Lukáš ; Musílek, Kamil (advisor) ; Farsa, Oldřich (referee) ; Zimčík, Petr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Lukáš Hroch Supervisor assoc. prof. PharmDr. Kamil Musílek, Ph.D. Title of Doctoral Thesis Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease There were about 50 million people living with dementia in 2015. It is expected that number of people living with dementia will reach 130 million by the year of 2050. Alzheimer's disease (AD) is one of the most common causes of dementia and it is estimated to account for about 60 80% of overall cases. Current symptomatic treatment only alleviates symptoms and delays progression of the disease. However, there is no effective treatment, which would address the underlying cause of AD. The extracellular depositions of insoluble amyloid beta peptide (Aβ) were thought to be a causative factor and main target for a long time. Yet, targeted treatment towards the reduction of extracellular Aβ depositions failed to show expected therapeutic merit. Later on, it has been shown that development of AD starts much earlier than any Aβ plaques or symptoms could be observed. With growing evidence of soluble Aβ in intracellular regions, main attention moved to investigations of Aβ within the cells. Aβ...
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Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease
Hroch, Lukáš ; Musílek, Kamil (advisor) ; Farsa, Oldřich (referee) ; Zimčík, Petr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Lukáš Hroch Supervisor assoc. prof. PharmDr. Kamil Musílek, Ph.D. Title of Doctoral Thesis Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease There were about 50 million people living with dementia in 2015. It is expected that number of people living with dementia will reach 130 million by the year of 2050. Alzheimer's disease (AD) is one of the most common causes of dementia and it is estimated to account for about 60 80% of overall cases. Current symptomatic treatment only alleviates symptoms and delays progression of the disease. However, there is no effective treatment, which would address the underlying cause of AD. The extracellular depositions of insoluble amyloid beta peptide (Aβ) were thought to be a causative factor and main target for a long time. Yet, targeted treatment towards the reduction of extracellular Aβ depositions failed to show expected therapeutic merit. Later on, it has been shown that development of AD starts much earlier than any Aβ plaques or symptoms could be observed. With growing evidence of soluble Aβ in intracellular regions, main attention moved to investigations of Aβ within the cells. Aβ...
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Preparation of 3,5,5-Trisubstituted Hydantoins From Activated Cbz-Aminomalonic Acids
Hroch, Lukáš ; Doležal, Martin (advisor) ; Zimčík, Petr (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Supervisor: Prof. Dr. Michael Gütschow Candidate: Lukáš Hroch Title of diploma thesis: Preparation of 3,5,5-Trisubstituted Hydantoins From Activated Cbz-Aminomalonic Acids Hydantoins are of notable importance for drug discovery. Their utilization arises from their scaffold, which offers three distinct positions for possible substitution with a wide range of residues. Accordingly, they can act as biologically active compounds in different ways. The aim of the work was to continue with the project started by M. Hrušková. The unexpected formation of 5-ethyl-3-phenyl-5-(phenylcarbamoyl) hydantoin encouraged the efforts to more deeply explore the potential of the reaction by preparing more of 3,5,5-trisubstituted hydantoins. Preparation of Cbz-aminomalonic acids started with the protection of the amino group of diethyl 2-aminomalonate hydrochloride. Diethyl 2-(benzyloxycarbonylamino) malonate 4 was alkylated and consequently diethyl 2-alkyl-2- (benzyloxycarbonylamino)malonates 5 were saponified to afford 2-alkyl-2- (benzyloxycarbonylamino)malonic acids 6. Then, the activation with oxalyl chloride and treatment with primary aromatic amines followed. 3,5-Disubstituted...
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