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Synthesis, reactivity and biological activity of C5 substituted uracil analogues
Brulíková, Lucie ; Holý, Antonín (advisor) ; Rosenberg, Ivan (referee) ; Moravcová, Jitka (referee)
Bibliographical identification: Author's first name and surname: RNDr. Lucie Brulíková (nee Spáčilová) Title: Synthesis, reactivity and biological activity of C-5 substituted uracil analogues Type of thesis: Ph.D. thesis Department: Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc Advisor: prof. RNDr. Antonín Holý, Dr.Sc., Dr.hc. mult. Advisor-consultant: doc. RNDr. Jan Hlaváč, Ph.D. The year of presentation: 2011 Abstract: The presented thesis is focused on the synthesis of various C-5 modified uracil analogues, the study of their reactivity and biological activity, especially cytotoxic activity. In the first part, the brief survey of described results for selected 5-alkoxymethyluracil analogues is performed. The second part of the presented thesis deals with the synthesis of novel uracil analogues modified at the C-5 position, the development and optimizing of procedure leading to the desired compounds, the study of biological activity and the evaluation of structure- activity relationship (SAR). This part presents the synthesis of a series of 5-[alkoxy(4- nitrophenyl)methyl)]uracil and 5-alkoxymethyluracil analogues and extended SAR studies depending on a substitution of metylene bridge directly attached at the C-5 position as well as alkoxy chain length. The last part of...
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Acyclic nucleoside phosphonates with expanded purine bases
Čapková, Kateřina ; Holý, Antonín (advisor) ; Černý, Miloslav (referee) ; Kefurt, Karel (referee) ; Hocek, Michal (referee)
Univerzita Karlova Příro dovědecká fakulta Katedra organické a jaderné chemie Akademie věd Ceské Republiky Ústav organické chemie a biochemie S tirrltrffi[n Acyklické nukleo sidfo sfon áty rozšířenoupurinovou bazí Kateřina Čapková Shrnutí disertačnípráce Praha 2006 -tt ai-''- ffi-'.--.-/ /{ía' s Acyklické nukleosid fosfonáty předstalují velice zajimavou skupinu nukleotidových analogů s protivirovými, cýostatickj.rni a antiprotozoá|ními účinky.Jsou aktivní nejen proti širokému spektru DNA viru (herpesviry, poxviry, adenoviry, papillomaviry), ale i proti retrovirům (virus hepatitidy B, HIV). Nejvýznamnějšími představiteli celé skupiny jsou PMEA (adefovir, v klinické praxi ve formě adefovir dipivoxil), schválený pro léčbuhepatitidy B (HepseraTM), dále (fi).PMPA (teno-Qvir. v klinické praxi jako tenofovir disoproxil fumarát), schválený pro léčbuAIDS (Viread.'u') a (S)-HPMPC (cidofovir),-schválený pro léčbucýomegalovirové retinitidy u imunosuprimovaných pacientů (VistideTM). 1 V rámci hledání nových potenciálních virostatik a cýostatik bylo mým úkolem připravit série několika nových typůmodifikovaných acyklických nukleosid fosfonátů, konkrétně s tricyklickou bazi odvozenou od původnípurinové baze. Tricyk|ické baze23 ;so., zajímavé předevšímkvůli své fluorescencí,která umoŽňuje snadnou detekci a sledování osudu...
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Synthesis of oligosaccharides of Dhexosamine type-potential ligands of activating receptors of NK cells
Kovalová, Anna ; Ledvina, Miroslav (advisor) ; Černý, Miloslav (referee) ; Kefurt, Karel (referee) ; Holý, Antonín (referee)
stu(trd oÍgaŮáůr' ďthercce#*' lsťÍees€pd-e fuandffig sibs.. CoNcLusroN In the course of this work, we prepared oligosaccharides containing 2-acetamido-2- deoxyglucopyranose and 2-acetamido-2-deoxygalactopyranose units and tested them for binding to NK cell receptors NKR-p1 and CD69. Branched oligosaccharides are first effective mimetics of natural ligands of CD69. We successfully completed the synthesis despite some challenging problems (multiple glycosylations, H-bonds), and we also obtained results, which contribute to the understanding of a relevant biological question. APLICABILITY AND PERSPECTIVES Although the synthesized o|igosaccharides were speciÍica||y designed as |igands for lectin receptors of NK cells, they may have other uses too. We intend to introduce linkers to the reducing position of the oligosaccharides to enable their presentation on dendrimeric structures. These multiple glycodendrimers can substitute natural multiantenar ligands. Moreover, oligosaccharides of this type might be used as a part of vector systems of new generation targeted combined chemo- and immunotheraoeutics. This Work was suppofted by grants No. 241/2013/B-CH/PřF and 416/2004/B-CH/PřF of GAUK' No. QF31 1 5/2003 of Ministry of Agricutture of cR, 203/00/0071 of Grant Agency of cR, by research project No 24 055 05O6.and...
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Synthesis of purine and pyrimidine derivatives with potential biological activities.
Jansa, Petr ; Holý, Antonín (advisor) ; Černý, Miloslav (referee) ; Rosenberg, Ivan (referee)
An extensive overview of the current state of the research in the field of the development of acyclic nucleoside phosphonates (ANPs) was elaborated, which quotes from 196 publications in abstracted journals. A new microwave-assisted methodology for the preparation of dialkyl haloalkylphosphonates was developed. Through strict control of the reaction temperatures in microwave reactor, it was possible to lower the amount of the reactants all the way to the ideal ratio of 1:1. With the use of a continuous-flow microwave reactor, it was possible to prepare the key building blocks for the subsequent syntheses of ANPs in large quantities (100 g), which significantly accelerates research in this area. The new method was patented and published. While studying various ANP prodrugs, a new highly effective methodology for the preparation of the diamides of ANPs was developed. The method starts directly from ANP diesters, which react with trimethylsilylbromide to form the corresponding bis(trimethylsilyl)esters of ANPs, which are well soluble in organic solvents and react smoothly during the subsequent introduction of aminoacid esters. Moreover, the reaction with trimethylsilylbromide protects the reactive groups present in the rest of the molecule and thus prevents undesired side reactions. Furthermore, using...
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Synthesis, reactivity and biological activity of C5 substituted uracil analogues
Brulíková, Lucie ; Holý, Antonín (advisor) ; Rosenberg, Ivan (referee) ; Moravcová, Jitka (referee)
Bibliographical identification: Author's first name and surname: RNDr. Lucie Brulíková (nee Spáčilová) Title: Synthesis, reactivity and biological activity of C-5 substituted uracil analogues Type of thesis: Ph.D. thesis Department: Department of Organic Chemistry, Faculty of Science, Palacký University Olomouc Advisor: prof. RNDr. Antonín Holý, Dr.Sc., Dr.hc. mult. Advisor-consultant: doc. RNDr. Jan Hlaváč, Ph.D. The year of presentation: 2011 Abstract: The presented thesis is focused on the synthesis of various C-5 modified uracil analogues, the study of their reactivity and biological activity, especially cytotoxic activity. In the first part, the brief survey of described results for selected 5-alkoxymethyluracil analogues is performed. The second part of the presented thesis deals with the synthesis of novel uracil analogues modified at the C-5 position, the development and optimizing of procedure leading to the desired compounds, the study of biological activity and the evaluation of structure- activity relationship (SAR). This part presents the synthesis of a series of 5-[alkoxy(4- nitrophenyl)methyl)]uracil and 5-alkoxymethyluracil analogues and extended SAR studies depending on a substitution of metylene bridge directly attached at the C-5 position as well as alkoxy chain length. The last part of...
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Synthesis and properties of Chiral Acyclic Nucleoside Bisphosphonates and Phosphonomethylphoshinates
Doláková, Petra ; Holý, Antonín (advisor) ; Trnka, Tomáš (referee) ; Moravcová, Jitka (referee) ; Hocek, Michal (referee)
Charles University, Faculty of Science Department of Organic and Nuclear Chemistry Synthesis and Properties of Chiral Acyclic Nucleoside Bisphosphonates and Phosphonomethylphosphinates Doctoral Thesis Abstract Mgr. Petra Doláková Advisor: Prof. Dr. Antonín Holý, DrSc., Dr.h.c. mult. Academy of Sciences of the Czech Republic Institute of Organic Chemistry and Biochemistry Prague 2008 Přírodovědecká fakulta Univerzity Karlovy v Praze Katedra organické a jaderné chemie Syntéza a vlastnosti chirálních bisfosfonátů a fosfonomethoxyfosfinátů acyklických analogů nukleosidů Autoreferát disertační práce Mgr. Petra Doláková Školitel: Prof. Dr. Antonín Holý, DrSc., Dr.h.c. mult. Ústav organické chemie a biochemie, AV ČR, v.v.i. Praha 2008 Introduction Acyclic nucleoside phosphonates (ANPs) represent a key class of nucleotide analogs with a broad spectrum of antiviral and cytostatic activity.1 Among ANPs, particularly 9-[2- (phosphonomethoxy)ethyl]adenine (PMEA, adefovir, Figure 1) is active against DNA and retroviruses; its prodrug, adefovir dipivoxil, was approved for hepatitis B therapy (Hepsera). 9-(R)-[2-(Phosphonomethoxy)propyl]adenine (PMPA, tenofovir), is a promising anti-HIV drug, its prodrug Viread was approved for treatment of AIDS and chronic hepatitis B. A third type of antiviral compounds is represented...
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