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Design and Synthesis of Prodrugs of 6-Diazo-5-oxo-L-norleucine; Potential Treatment for Glioblastoma
Novotná, Kateřina ; Majer, Pavel (advisor) ; Rýček, Lukáš (referee)
6-Diazo-5-oxo-L-norleucine (DON, 1) is a non-standard amino acid with proven antitumor activity found in soil bacteria of the genus Streptomyces. However, due to the considerable systemic toxicity manifested mainly in the gastrointestinal tract, DON alone is not a suitable clinical candidate for the treatment of cancer. One of the ways to solve the problem of its toxicity is the reversible structural modification of this molecule by protecting both its amino group and carboxyl functional group, by preparing the so-called prodrug of DON. The prepared prodrug may suitably alter the distribution of DON in the body and at the same time increase its permeability to brain tissue. Due to this structural modification, its side effects can be eliminated and a substance for the treatment of brain tumors, such as glioblastoma multiforme (GBM), can potentially be formed. In my dissertation, five strategies for the specific delivery of DON to the brain using different types of its prodrugs are discussed. The new prodrugs are designed to be either capable of spontaneous penetration across the blood-brain barrier or of being a substrate for one of its influx transporters. At the same time, these prodrugs should be stable in other metabolically active organs and blood plasma in order to sufficiently reduce the...
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Design and Synthesis of Prodrugs of 6-Diazo-5-oxo-L-norleucine; Potential Treatment for Glioblastoma
Novotná, Kateřina ; Majer, Pavel (advisor) ; Rýček, Lukáš (referee)
6-Diazo-5-oxo-L-norleucine (DON, 1) is a non-standard amino acid with proven antitumor activity found in soil bacteria of the genus Streptomyces. However, due to the considerable systemic toxicity manifested mainly in the gastrointestinal tract, DON alone is not a suitable clinical candidate for the treatment of cancer. One of the ways to solve the problem of its toxicity is the reversible structural modification of this molecule by protecting both its amino group and carboxyl functional group, by preparing the so-called prodrug of DON. The prepared prodrug may suitably alter the distribution of DON in the body and at the same time increase its permeability to brain tissue. Due to this structural modification, its side effects can be eliminated and a substance for the treatment of brain tumors, such as glioblastoma multiforme (GBM), can potentially be formed. In my dissertation, five strategies for the specific delivery of DON to the brain using different types of its prodrugs are discussed. The new prodrugs are designed to be either capable of spontaneous penetration across the blood-brain barrier or of being a substrate for one of its influx transporters. At the same time, these prodrugs should be stable in other metabolically active organs and blood plasma in order to sufficiently reduce the...
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Synthesis of prodrugs of glutamine antimetabolite 6-diazo-5-oxo-L-norleucine
Novotná, Kateřina ; Majer, Pavel (advisor) ; Machara, Aleš (referee)
The 6-diazo-5-oxo-L-norleucine (DON) is a glutamine antimetabolite, which has shown promissing antitumor activity in preclinical and several clinical studies. However, its high toxicity leading to gastrointestinal side effects prevented its further development. The aim of this Bachelor thesis was to prepare DON prodrugs with similar anticancer activity but less side effects. Biochemical and biological tests of synthesized prodrugs were performed at Johns Hopkins University in Baltimore (USA). Key words: 6-diazo-5-oxo-L-norleucine (DON), prodrugs, antimetabolite, ProTide
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Overcoming drug resistance: The discovery, design and characterization of new nonpeptidic inhibitors of HIV - 1 protease
Kožíšek, Milan ; Konvalinka, Jan (advisor) ; Majer, Pavel (referee) ; Obšil, Tomáš (referee)
Ph.D. thesis abstract Overcoming drug resistance : The discovery, design and characterization of new nonpeptidic inhibitors of HIV-1 protease Milan Kožíšek, M.Sc. Supervisor : Jan Konvalinka, Ph.D. PPrraagguuee 22001100 Department of Biochemistry Faculty of Science Charles University, Prague, Czech Republic Institute of Organic Chemistry and Biochemistry Gilead Sciences & IOCB Research Centre Academy of Sciences of the Czech Republic 3 Abstract HIV-1 protease is an aspartic protease which plays an essential role in the life cycle of HIV virus. It is responsible for the cleavage of the viral polyproteins into the structural and functional proteins during viral maturation. The efficient inhibition of the protease thus leads to the formation of immature and non-infectious viral particles. The introduction of protease inhibitors dramatically changed the treatment of retroviral infection. The viral replication was reduced to undetectable level and the rate of disease progression was significantly lowered. However, resistance to the inhibitors was observed. The first inhibitors had limited bioavailability, caused severe side effects and easily developed resistance. To combat these negative factors, second-generation inhibitors have been developed. Understanding the mechanisms of resistance toward inhibitors is...
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