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Study of transalkylation of tert-butylsulfides
Kolenič, Marek ; Zimčík, Petr (advisor) ; Kučerová, Marta (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Mgr. Marek Kolenič Consultant: assoc. prof. PharmDr. Petr Zimčík, Ph.D. Title of Thesis: Study of transalkylation of tert-butylsulfides Novel, atypical and unexpected transalkylation reaction was discovered during the synthesis of highly substituted phthalocyanines. This thesis follows up with previous research and examines effect of peripheral substitution on the course of above-mentioned transalkylation reaction at tert-butysulfides. For this purpose, total six derivatives with both electrondonating and electronaccepting groups, with pyrazine core and also without any substitution, were synthesised and used. Conversion ratio to corresponding aromatic methylsulfides after reaction with methyliodide was analyzed and evaluated by 1 H NMR spectroscopy (via aliphatic signals integration). Compounds with electrodonating groups gave higher reaction rates, on the other hand electronaccepting groups made reaction slower, in extreme cases no product was even observed. One pyrazine derivative gave us new, unpublished molecule via direct N-alkylation of pyrazine instead of transalkylation reaction.
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Synthesis and biological evaluation of dimefluron and benfluron derivatives
Kolenič, Marek ; Špulák, Marcel (advisor) ; Roh, Jaroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Marek Kolenič Consultant: PharmDr. Marcel Špulák, Ph.D. Title of Thesis: Synthesis and biological evaluation of dimefluron and benfluron derivatives Benflurone is an original Czechoslovak cytostatic drug developed at Research Institute of Pharmacy and Biochemistry (VÚFB). Due to its unfavorable pharmacokinetic properties it has not been used for human therapy of cancer. Dimeflurone, developed with aim to improve pharmacokinetics of benflurone, was discontinued either at the phase of preclinical trials. Disadvantageous properties of both drugs is caused by rapid deactivation leading to formation of nearly inactive 7-hydroxyderivatives. In my diploma thesis, I concern about synthesis, in vivo and in vitro biological evaluation of C7-derivatives of both compounds. We assume lower deactivation rate and also longer and more potent effect. Firstly, sufficient amount of dimeflurone had to be synthesized, this process was improved and scaled-up. Although all the derivatives are more cytotoxic on cell lines MCF-7, BT-549 and MDA-MB-231 and they are also less toxic in mice after p.o. administration, they do not reduce weight of solid Ehrlich tumor neither prolong time of survival.
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