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Current trends in the development of steroidal hormones modulators
Lioudakis, Emmanouil ; Opletalová, Veronika (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Emmanouil Lioudakis Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Diploma Thesis: Current trends in the development of steroidal hormone modulators Steroidal hormone modulators are considered to be both effective and vital agents concerning the treatment of various types of cancer, as well as playing a crucial role in the regulation of a wide range of physiological actions. Since the development of the very first modulators, a significant progress has been made regarding the development of new ones with limited adverse effects. The current thesis provides information concerning older drugs and recent data about them. In addition, new drugs which are under clinical trials are described and their structures are referred. New drugs have been developed in order to be safer and more efficient than older ones. A lot of promising agents which are considered as a successful alternative treatment and carry less risk are either already approved or will be accepted in the near future.
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Synthesis of functional derivatives of malonic acid as building blocks for elastase-inhibitors
Hrušková, Marie ; Opletalová, Veronika (advisor) ; Cahlíková, Lucie (referee)
Rheinische Friedrich-Wilhelms University Bonn The Faculty of Mathematics and Natural Sciences Pharmaceutical Institute, Pharmaceutical Chemistry I Diploma Thesis Synthesis of Functional Derivatives of Malonic Acid as Buildings Blocs for Elastase Inhibitors Marie Hrušková Human leukocyte elastase (HLE) is a serine protease, which plays an important role in inflammatory diseases. Low molecular weight inhibitors can be therapeutically used for example for the treatment of chronic obstructive pulmonary diseases. In this thesis, azetidin- 2,4-dione derivatives should be prepared as HLE inhibitors. In particular, 3- (benzyloxycarbonylamino)-3-ethyl-N-phenyl-azetidine-2,4-dione should be synthesized. The protected amino group was expected to increase the peptidic character of this molecule and thus, affinity to HLE. The starting compound was 2-aminomalonic acid diethylester hydrochlorid. The amino function was protected in the first step, followed by alkylation and then hydrolysis of 2- (benzyloxycarbonylamino)-2-ethylmalonic acid diethylester to 2-(benzyloxycarbonylamino)- 2-ethylmalonic acid. Both the ester of 2-(benzyloxycarbonylamino)malonic acid and the 2-(benzyloxycarbonyl-amino)ethylmalonic acid showed in their 1 H NMR spectra a multiplet in place of the expected quartet. This phenomenon was...
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Synthesis of novel acetylcholinesterase reactivators bearing various linkers between two pyridinium rings.
Hambálek, Jan ; Doležal, Martin (advisor) ; Opletalová, Veronika (referee)
Synthesis of novel acetylcholinesterase reactivators bearing various linkers between two pyridinium rings Summary Six novel bispyridinium AChE reactivators with aliphatic linker and nine novel reactivators with xylene linker were synthesized. Their ability to reactivate AChE inhibited by nerve agent tabun and insecticide paraoxon was tested in vitro. pralidoxime, HI-6 a obidoxime were chosen as reference compounds. Regarding the obtained results, six compounds seem to be potent reactivators of paraoxon-inhibited AChE for both chosen concentration. Furthermore, there is evidence that compounds with only one hydroxyiminomethyl group with xylene linker have also reactivation ability compared to bisoxime compounds. Reactivation potency is decreasing with increasing length of the aliphatic linker. None of the tested compounds was able to reactivate tabun-inhibited AChE.
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Synthesis and biological evaluation of purine inhibitors of phosphatidylinositol 3-kinases and related protein kinases II.
Vejrychová, Kateřina ; Opletalová, Veronika (advisor) ; Kučerová, Marta (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Kateřina Vejrychová Supervizor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Consultant: Mgr. Martin Andrš Title of diploma thesis: Synthesis and biological evaluation of purine inhibitors of phosphatidylinositol-3-kinases and related protein kinases II Cancer is a serious disease with an uncertain prognosis and difficult treatment. Nowadays, cancer is one of the most common causes of death worldwide. Options of therapies are evolving every year; nevertheless, we still do not have effective treatment available for all types of tumours. Patients often undergo conventional cytotoxic therapy or radiotherapy, which unfortunately have many side effects and they are not always effective. One of the highly researched ways how to make this treatment more effective is to disrupt corrective mechanisms of DNA damage, which are the essence of radiotherapy and some chemotherapeutics. For this purpose, phosphatidylinositol-3-kinase-related proteinkinases, especially DNA-dependent proteinkinase (DNA-PK) seem to be very useful, because they are highly involved in DNA repair. In this diploma thesis, 12 potential inhibitors of DNA- PK were prepared, from which 9 substances were tested alone on 9...
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Application of Pd-Catalyzed Reactions to the Synthesis of Lactones
Šnajdr, Ivan ; Pour, Milan (advisor) ; Kotora, Martin (referee) ; Opletalová, Veronika (referee)
Within the framework of this Thesis, a method fot the preparation of 3,6- disubstituted pyranones was developed and 15 final lactones were synthesized, and their cytostatic and antifungal activity was investigated. Principal steps in the preparation of the compounds were Yamaguchi-Hirao alkylation, hydroalumination followed by iodation and Pd- catalyzed carbonylative lactonization. None of the target compounds displayed interesting cytostatic or antifungal activity (IC50 < 10 μmol/L), which was suprising given the significant antifungal activity of analogous butenolides. The development of the synthesis of 3- monosubstituted pyranones is described next. Our strategy is based on the use of 5,6-dihydro-2H- pyran-2-one as the starting material, which was converted into the 3-iodo-5,6-dihydro-2H- pyran-2-one in one step. The key step of the synthesis was Pd-catalyzed Suzuki coupling. Finally, the preparation of α- and β-substituted-γ-alkylidenepentenolides is described. The target compounds exhibited significant cytostatic activity (IC50 < 5 μmol/L) against all tested tumor cells (CCRF-CEM, HeLa S3, HT 29, HL 60, L 1210).
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Synthesis of carboxyxanthone derivatives as building blocks for enantiomeric pure compounds. Synthesis and structure elucidation of xanthone derivative (XD) 2-carboxy-6-methoxyxanthone (XD-2)
Heczková, Jana ; Opletalová, Veronika (advisor) ; Zimčík, Petr (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Jana Heczková Consultant Professora Doutora Madalena Maria de Magalhães Pinto, Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis Synthesis of carboxyxanthone derivatives as building blocks for enantiomeric pure compounds. Synthesis and structure elucidation of xanthone derivative (XD) 2-carboxy-6-methoxyxanthone (XD-2) The importance of xanthone derivatives is considerable. They possess large variety of biological and pharmacological activities. Many of them proved to be important building blocks for synthesis of new compounds. Chirality is a fundamental property of biological systems and reflects the underlying asymmetry of matter. Almost one-third of all drug sales worldwide are chiral compounds and the authorities recommend that the chiral drugs should be saled in pure enantiomeric forms because enantiomers may differ both quantitatively and qualitatively in their biological activities. At one extreme, one enantiomer may be devoid of any biological activity; at the other extreme, both enantiomers may have qualitatively different biological activities. Enantiomers also differ in bioavailability - one enantiomer can be more bioavailable than the other,...
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Pyrazine derivates as potential drugs I.
Klusoňová, Petra ; Doležal, Martin (advisor) ; Opletalová, Veronika (referee)
Title of diploma thesis: Pyrazine derivatives as potential drugs I. Review of actual worldwide problem of tuberculosis and trends in the tuberculosis treatment and chemical recherché were the parts of this work. Novel pyrazine derivatives connected via -CONH- bridge with substituted anilines were synthesized. The synthetic approach, analytical, spectroscopic, lipophilicity and biological data of twelve newly synthesized compounds were presented. All products were characterized and tested against Mycobacterium tuberculosis strain H37Rv and against eight fungal pathogen strains. Additionally, the study of inhibition of oxygen evolution rate in spinach chloroplasts and reduction of chlorophyll content in the green algae Chlorella vulgaris in the series of prepared compounds were drawn. Structure-activity relationships among the chemical structure, lipophilicity (log P), and their biological activity of the evaluated compounds were discussed as well.
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Synthesis of monoquarternary pyridinium reactivators of acetylcholinesterase
Kučera, Jiří ; Opletalová, Veronika (advisor) ; Doležal, Martin (referee)
Kučera, J.: Synthesis of monoquaternary pyridinium reactivators of acetylcholinesterase. Diploma Thesis. Charles University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry and Drug Control, Hradec Králové 2008 Summary Organophosphates are substances commonly used in agriculture as pesticides (metathione, malathione, Actellic, In-stop), in industry as hydraulic liquids, plasticizers, flame retardants. They are also used in human and veterinary medicine as drugs or for examination of neurological functions. Nerve agents are based on the same chemical structure. It is relatively easy and cheap to produce them, to use them for military purposes and misuse them by terrorist organizations. There are frequent intoxications of labourers in agriculture or in industry as well. Present treatment of organophosphate intoxication includes administration of acetylcholinesterase reactivators, atropine and diazepam. None of the currently available commercial reactivators is able to reactivate satisfactorily acetylcholinesterase inhibited by different types of organophosphates. The aim of the work was the synthesis and in vitro testing of new compounds with hypothesized reactivation efficiency.
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Derivatives of Rhodanine as Potential Drugs I
Kešetovičová, Diana ; Opletalová, Veronika (advisor) ; Kučerová, Marta (referee)
Diploma thesis title: RHODANINE DERIVATIVES AS POSSIBLE THERAPEUTICS I. Author: Diana Kešetovičová ABSTRACT The raise of microbial resistance towards commonly used antimicrobial agents enhances the need for new active substances with novel modes of action. Rhodanine (2-thioxo-1,3-thiazolidin-4-one) represents a structural motif that has not yet been applied in any antimicrobial drug. Rhodanine derivatives have already been described as substances possessing a wide spectrum of biological activity. Within this diploma thesis, condensation products of rhodanine and 3-(2- hydroxyethyl)-rhodanine with ortho-, meta- and para-substituted nitro- benzaldehydes have been prepared. The reaction was carried out in water- alcoholic medium using NH4OH/NH4Cl as a catalyst. The antifungal and antimycobacterial properties of these derivatives and their inhibitory activity on photosynthetic processes were then evaluated. A medium antifungal activity against C. albicans, T. asahii, T. mentagrophytes and A. fumigatus have been observed with the N-unsubstituted derivatives, while the N-substituted derivatives were inactive. The antimycobacterial properties of the tested compounds were not high enough (inhibition of at least 90% in the primary test) to undergo further studies. The antimycobacterial activity of the N-substituted...
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