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Analysis of farnesylated peptides and proteins using LC-MS
Hessler, Filip ; Kovaříková, Petra (referee) ; Waisser, Karel (advisor)
Farnesylated proteins are important in transduction of signals in cell and therefore can figure in development of many diseases, mainly cancer. Electrospray mass spectrometry is a widely used method in analysis of peptides and proteins, thus it was chosen as a method to develop a simple way to detect farnesylated proteins in cell. A cleavage pattern of these proteins, when subjected to MS/MS, was found on examples of synthetically farnesylated simple peptides and bovine albumin. Distinctive features of MS/MS spectra of these peptides are two peaks, which both represent the virgin peptide fragment after the farnesyl moiety was cleaved off. These fragments have a different charge, because they originate from different type of cleavage. Homological cleavage of the bond between the farnesyl and sulfur leads to formation of a new charge on the peptide fragment, while the leaving farnesyl is also charged and has amu of 205. Second type of fragment rises from neutral loss of farnesyl moiety, there is no new charge generated on the peptide fragment and the amu of the leaving farnesyl moiety is 204, because it looses one of its hydrogen in favor of the peptide. This knowledge can be applied also to more complicated protein samples prepared from cells. When searching for farnesylated proteins in such a...
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Development of new group of potential antituberculotics
Divišová, Hana ; Waisser, Karel (advisor) ; Kolář, Karel (referee)
In this rigorous paper three problems were solved: a) synthesis and antimycobacterial activity of new halogenated salicylanilides substituted in position 4' with branch chain. b) synthesis and antimycobacterial activity of new halogenated 3-(4-alkylphenyl)-1,3-benzoxazine-2,4-(3H)-diones. c) influence of replacement of oxo group by thioxo group in the previously group of compounds. a) It was synthesized 8 halogenated derivatives of 4'-alkylsalicylanilides with branched alkyl chain. These compounds were evaluated in vitro on antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. b) It was synthesized 7 halogenated derivatives of benzoxazinediones with branch chain by reaction of salicylanilides with methylchloroformiate. Antimycobacterial activity of synthesized compounds was evaluated against three different mycobacterial strains. The most active compound was 7- chloro-3-(4-sec-butylphenyl)-1,3-benzoxazine-2,4-(3H)-dione. c) There were synthesized the following compounds: 7-chloro-3-(4-isopropylphenyl)-4-thioxo-2H-1,3- benzoxazine-2(3H)-one, 6-bromo-3-(4-isopropylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-one, 6- bromo-3-(4-sec-butylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-one, 6-chloro-3-(4-sec-...
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New groups of potential antibuberculotics
Adamec, Jan ; Waisser, Karel (advisor) ; Lešetický, Ladislav (referee) ; Čižmárik, Jozef (referee)
9. Summary This work is focused on the synthesis and biological evaluation of the derivatives of 1-aryl-5-(benzylsulphanyl)tetrazole and group of hybrid molecules of estrone. It has been found before that alkylsulphanyl group bound to an electron deficient carbon of heterocyclic system represents a pharmacophore responsible for a significant antimycobacterial activity. It has been reported that some antimycobacterial compounds are often antifungal as well. The study is subdivided into three parts. The first one compares the antimycobacterial activity of a group of derivatives of 1-aryl-5-(alkylsulphanyl)tetrazole derivatives (where ethyl, propyl, iso-propyl or allyl stands for the alkyl) and 1-aryl-5-(benzylsulphanyl)tetrazole. The benzyl derivatives exhibited significantly better activity, which was further confirmed by the QSAR analysis. Concerning the group of benzyl derivatives, it was observed that, substitution on the benzyl moiety leads to lower activity. The second studied subject was the antifungal activity of the prepared 1-aryl-5-(benzylsulphanyl)tetrazoles evaluated on eight clinically important fungal strains. The activity was negligible with the exception of Trichophyton mentagrophytes. By means of QSAR analysis, it was found out in the studied group that the increase in the lipophility causes...
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Antimycobacterial isosters of salicylanilides
Matyk, Josef ; Waisser, Karel (advisor) ; Čižmárik, Jozef (referee) ; Lešetický, Ladislav (referee)
V PhD disertaci byla popsána skupina 79 látek (4-alkylfenyl)salicylamidů, N-heteroarylsalicylamidů, 3-(4-alkylfenyl)-2H-1,3-benzoxazin-2,4(3H)-dionů, 3- (4-alkylfenyl)-2H-1,3-bemzoxazin-4(3H)thioxo-2-onů, 3-(4-alkylfenyl)-2H-1,3- benzoxazin-2,4(3H)-dithionů a 3-heteroaryl-2H-1,3-benzoxazin-2,4(3H)-dionů. Látky byly hodnoceny na antimykobakteriální, antifungální a antibakteriální aktivitu. Vybrané látky byly hodnoceny na cytotoxicitu. Deriváty (4-alkylfenyl)salicylamidů byly analyzovány přístupem QSAR (Kvantitativní vztahy mezi strukturou a aktivitou) a to metodou podle Freeho a Wilsona. Struktura připravených látek byla ověřena 1 H-NMR a IČ-spektroskopií a jejich čistota elementární analýzou. Deriváty (4-alkylfenyl)salicylamidů, N-heteroarylsalicylamidů, 3-(4- alkylfenyl)-2H-1,3-benzoxazin-2,4(3H)-dionů, 3-(4-alkylfenyl)-2H-1,3- bemzoxazin-4(3H)thioxo-2-onů, 3-(4-alkylfenyl)-2H-1,3-benzoxazin-2,4(3H)- dithionů a 3-heteroaryl-2H-1,3-benzoxazin-2,4(3H)-dionů vykazovaly vysokou aktivitu vůči Mycobacsterium tuberculosis a atypickým kmenům mykobaktérií (M. avium a M. kansdasii).
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4'-alkylsalicylanilides with branched aliphatic chain and the corresponding derivatives of benzoxazinedions
Divišová, Hana ; Waisser, Karel (advisor) ; Kuneš, Jiří (referee)
Three problems of antimycobacterial compounds were solved in the work. a) It was synthesis of eight new halogenated 4' -alkylsalicylanilides with branched alkyl in position 4'. b) Synthesis of new halogenated 3-(4-alkylphenyl)-1,3-benzoxazin-2,4-(3H)-diones. ) with the branched alkyl on the phenyl. Seven new halogenated 3-(4-alkylphenyl)-1,3-benzoxazin-2,4-(3H)- diones were synthesized by reaction of salicylanilides and methyl choroformiate. All the compounds were screened in vitro against three different strains of mycobacterium. The results were not finished at the time of diploma work. We assume according hypothesis of professor Waisser that the activity of the new compounds will be very perspective. .
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New groups of potential antituberculotics with thioxo group
Husáková, Petra ; Waisser, Karel (advisor) ; Kolář, Karel (referee)
. ENGLISH ABSTRACT In the rigorous thesis are described the influence of replacement oxo group for thioxo group in the series of halogenated 3-(4-ethylphenyl)benzoxazine-2,4(3H)-diones and 6-chloro-3- (4-butylphenyl)benzoxazine-2,4(3H)-dione. The starting ethyl (or butyl) salicylanilides were synthesis from substituted salicylic acid and ethyl (or butyl) aniline in toluene by the presence of phosphorus trichloride. (The set of halogenated salicyl acids compounds: 4-chloro-, 5-chloro-, 5- bromo- and 3,5-dibromosalicylic acid). The halogenated 4'-ethylsalicylanilides were reacted in dry pyridine with methyl-chloroformiate to form 3-(4-ethylphenyl)benzoxazine-2,4(3H)-diones. Similar were prepared 6-chloro-3-(4-butylphenyl)benzoxazine-2,4(3H)-diones. The mixture of 3- (4-ethyphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-one and 3-(4-ethylphenyl)-2H-1,3- benzoxazine-2,4(3H)-dithione was prepared by the reaction of the halogenated 3-(4- ethylphenyl)- 2H-1,3-benzoxazine-2,4(3H)-diones with phosphorus pentasulfide. The products were separated by chromatography. The 3-(4-ethylphenyl)-6-chloro-4-thioxo-2H-1,3- benzoxazine-2(3H)-ones and 6-chloro-3-(4-ethylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones were prepared by similar way. The compounds were tested in vitro for antimycobacterial activity against Mycobacterium...
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