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Targeted azole prodrugs with antifungal activity
Černá, Lucie ; Baszczyňski, Ondřej (advisor) ; Sedláček, Ondřej (referee)
Invasive fungal infections (IFIs), mostly caused by Aspergillus or Candida species, represent a severe global threat. IFIs are serious diseases of great concern especially in immunocompromised patiens, annually leading to more than 1.7 million deaths.1 Despite its seriousness, there is insufficient amount of available antifungal therapeutics. Current antifungal treatments rely mainly on azole drugs which often suffer from increased toxicity, low bioavailability and drug resistance, among others.2 Therefore, we aim to develop novel antifungals in the form of azole prodrugs which would selectively target specific fungal enzymes and would ideally avoid undesired off-target effects. Our designed prodrugs contain selected azoles, modified by the attachement of a self-immolative (SI) linker to a specific carbohydrate through a glycosidic bond. Such glycosidic bond should undergo cleavage by extracellular fungal glycosidases, resulting in release of the azole drug directly at the site of fungal infection. Keywords: azole, antifungal, prodrug, targeted delivery
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Hyaluronan for targeted drug delivery
Ureš, Tomáš ; Vávrová, Milada (referee) ; Pekař, Miloslav (advisor)
Hyaluronic acid (hyaluronan, HA) is a linear polysaccharide formed from disacharide units containing N-acetyl-D-glucosamine and glucuronic acid. HA is present in almost all biological fluids and tissues. In many cancer cells there is an upregulation of CD44, a receptor that binds HA. The receptor CD44 collocates hyaluronan in the special way. The bioconjugates built-up from the cytotoxic substances and hyaluronan are called prodrugs. The prodrugs can be used for targeted drug delivery system. Their main advantage is there is no need to medicine so high doses of pharmaceuticals and their adverse side effects are minimized. Hyaluronan can be used as well as the intra-articulation injection by osteoarthritis. HA is also used as the nutrition of joints, by treatment for diverse dermatic lesions, the repair of scars and it can be the ingredient of eye drops and nasal sprays. The cosmetic manufactures add HA into anti-wrinkle creams and anti-aging care.
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Enzymy pro aktivaci protinádorových proléčiv
Kubináková, Nikol
The current issue of oncological therapy lies in its effectiveness and severe side effects. Despite the most modern devices available for treatment methods, cancer treatment is very challenging. Chemotherapy uses highly toxic substances, which results in side effects that can only aggravate the patient. These side effects very often limit the dose of the drug, so that it is not possible to achieve such a concentration that would completely eradicate the tumor in the body. The answer to the question of how to overcome or reduce the occurrence of side effects in cancer treatment is prodrug therapy, which includes less toxic substances/drugs. This therapy aims to target cytotoxic drugs to a non-toxic derivative or prodrug. Prodrugs are inactive and bioreversible derivatives of active drugs that function as a concept for improving active drugs. After administration of the prodrug, this prodrug is selectively activated by enzymes (Cytochromes P450), resulting in the regeneration of the toxic parent drug at the site of the tumor.
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Synthesis of model, self-immolative, phosphate-based linkers for delivery of oximes
Kárníková, Tereza ; Baszczyňski, Ondřej (advisor) ; Matoušová, Eliška (referee)
This bachelor thesis explores a possibility of preparation and usage of oxime prodrugs. Thesis aim is to deliver oximes by using self-immolative phosphorous-based linkers that undergo cyclization reaction, leading to the release of oxime from the phosphorous. For this purpose, model systems containing: (1) a photolabile DMNB group, or they could contain enzymatically activable ester group, (2) self-immolative arm with the phosphate core, and (3) oxime as the leaving group, were prepared. Acetophenone oxime, cyclohexanone oxime, and griseofulvin oxime were used as the model oximes. In particular, the synthesis of target molecules and their self-immolation (i.e., controlled breakdown) have been studied. These reactions were monitored by 31 P NMR spectroscopy. The stability study of the prepared substances in buffer solutions has also been performed. Key words: oxime, prodrug, self-immolation, self-immolative linkers, photoactivation
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Hyaluronan for targeted drug delivery
Ureš, Tomáš ; Vávrová, Milada (referee) ; Pekař, Miloslav (advisor)
Hyaluronic acid (hyaluronan, HA) is a linear polysaccharide formed from disacharide units containing N-acetyl-D-glucosamine and glucuronic acid. HA is present in almost all biological fluids and tissues. In many cancer cells there is an upregulation of CD44, a receptor that binds HA. The receptor CD44 collocates hyaluronan in the special way. The bioconjugates built-up from the cytotoxic substances and hyaluronan are called prodrugs. The prodrugs can be used for targeted drug delivery system. Their main advantage is there is no need to medicine so high doses of pharmaceuticals and their adverse side effects are minimized. Hyaluronan can be used as well as the intra-articulation injection by osteoarthritis. HA is also used as the nutrition of joints, by treatment for diverse dermatic lesions, the repair of scars and it can be the ingredient of eye drops and nasal sprays. The cosmetic manufactures add HA into anti-wrinkle creams and anti-aging care.
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Tyrosine-based prodrugs of acyclic nucleoside phosphonates
Tichý, Tomáš ; Pomeisl, Karel ; Krečmerová, Marcela ; McKenna, Ch. E.
Prodrug approach based on masking of a phosphonate function by ester linkage to a tyrosine promoiety has been developed. Results demonstrate that tyrosine is a promoiety providing drug conjugates with good chemical stability, bioavailability and efficient activation to active drug species. Another properties like metabolic stability and antiviral activity can be tuned by modification of the carboxyl function of the promoiety. Phosphonate monoester prodrugs were prepared by PyBOP coupling of a protected tyrosine promoiety with suitably derivatized phosphonate function of the parent drug. Phosphonate diester prodrugs were prepared by "synthon" approach, emloying alkylation of purine nucleobase with pre-prepared PME synthons bearing two protected tyrosine promoieties.
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