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Syntéza nového typu acyklických nukleosid fosfonátů a příprava proléčiv a systémů doručení léčiva / Synthesis of novel types of acyclic nucleoside phosphonates and preparation of prodrugs and drug delivery systems

First part of this thesis was focused on the previously overlooked field of C1'-branched acyclic nucleoside phosphonates (ANPs). Five diverse synthetic approaches were developed/optimized affording key 6-chloropurine intermediates bearing N9 -phosphonomethoxyethyl (PME) branched at C1' position in 2-4 steps. It was demonstrated that these intermediates can be further vastly diversified into ANPs bearing both natural and unnatural nucleobases. Single enantiomers as well as racemates of final C1'-branched ANPs (overall 48 final compounds) were prepared and selected compounds were evaluated with respect to their biological properties. The aforementioned ANPs showed no antiviral potency against studied viruses and only weak to moderate cytostatic activity. Adenine C1'-branched ANPs proved to be the most potent currently known inhibitors of Trypanosoma brucei adenine phosphoribosyl transferase (TbrAPRT), an enzyme involved in purine salvage pathway (PSP) of T. brucei. Further biological evaluation of prepared compounds is in progress. Second part of this thesis was focused on development of novel prodrug moieties with higher selectivity index (i.e. toxicity/potency ratio - SI) based on so-called ProTide prodrugs where phenol (present in ProTides) was replaced by tyrosine derivatives. Tenofovir was...

Identiferoai:union.ndltd.org:nusl.cz/oai:invenio.nusl.cz:453273
Date January 2021
CreatorsKalčic, Filip
ContributorsJaneba, Zlatko, Míšek, Jiří, Krečmerová, Marcela
Source SetsCzech ETDs
LanguageEnglish
Detected LanguageEnglish
Typeinfo:eu-repo/semantics/doctoralThesis
Rightsinfo:eu-repo/semantics/restrictedAccess

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