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Synthesis of a combinatorial compound library based on the double click reaction
Krutáková, Mária ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
(English) Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mária Krutáková Supervisor: Assoc. Prof. PharmDr. Jan Zitko, Ph.D. Title: Synthesis of a combinatorial compound library based on the double click reaction Click chemistry is a powerful tool in drug discovery. It is very efficient in creating compound libraries through the combinatorial methodology. The copper(I)-catalyzed 1,2,3-triazole- forming reaction between azides and terminal alkynes has become the gold standard of click chemistry due to high reaction efficiency, mild reaction conditions, chemo- and regioselectivities. The molecules with triazole moiety display a broad spectrum of favorable properties and have been used in the development of antibacterial, antiviral, anti-inflammatory, anticancer, and anti-tubercular agents. This work focused on preparing a compound library using double-click reactions. Firstly, we synthesized several compounds with two alkyne groups ("alkyne cores") and a diverse group of structurally simple azides. In the next step, one equivalent of alkyne core was reacted with two equivalents of all prepared azides. The reaction between each alkyne core and ten azides yielded 100 compounds. The prepared libraries of compounds were...
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Targeting of Viral Nanoparticles to CD44 via Hyaluronic Acid
Hustedová, Anna ; Španielová, Hana (advisor) ; Hubálek Kalbáčová, Marie (referee)
Hyaluronic acid (HA) is widely studied as a targeting moiety to CD44 overexpressing cancer cells. Various types of nanoparticles (NPs) were modified by HA. Virus-like particles (VLPs) derived from mouse polyomavirus are an interesting class of NPs that can be modified by various targeting agents to increase their potential as gene or drug delivery vehicles for e.g. theragnostic purposes. HA has not been tested as a targeting moiety on VLPs, hence this was the focus of the current study. HA (~14 kDa) was attached to the VLPs via a bispecific Bodipy-derived fluorescent probe. To test the targeting potential of HA on comparable non-viral NPs, nanodiamonds were prepared in a similar manner. NPs functionalized with HA, together with Bodipy-labeled control variants, were tested on interactions with MDA-MB-231 cells overexpressing CD44. The NP-cell interaction via CD44 was assessed by a competitive cell-binding assay, where non-labeled HA competed for HA-binding sites at CD44 with the NPs. CD44 specific cell interactions were detected in studies with HA functionalized nanodiamonds, whereas VLP-HA* associated with cells in a less specific manner. Control VLPs with polyethylene glycol (PEG) did not interact with the cells. Results indicate that the HA targeting strategy for the VLPs requires optimization to...
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