This thesis is engaged in the synthesis of polysubstituted pyrimidines with anti- inflammatory properties. Such molecules can inhibit production of prostaglandin E2 (PGE2). The aim of this study was to enhance water-solubility and anti-inflammatory efficacy of such derivatives via structural modifications of the lead scaffold. Among applied synthetic tools, the Suzuki-Miyaura cross-coupling was the prevalent reaction, however, many other synthetic procedures (Heck reaction, condensation, borylation, ozonolysis, nucleophilic substitution, etc.) were utilized as well. Overall, 43 final products were prepared. The anti-inflammatory efficacy (inhibition of PGE2 production) was successfully increased as the most potent compound achieved three orders of magnitude higher activity compared to the current lead structure WQE-134. Furthermore, no general influence of the length of the substituent in the C5 position of pyrimidine (C5pyr) on the anti-inflammatory efficacy of synthesized compounds was observed. Significant bioavailability obstacle in future development of the current lead WQE-134 is its poor solubility which was successfully enhanced by introduction of heteroatom bearing moieties to C5pyr. The most water-soluble compound achieved two orders of magnitude higher solubility than WQE-134 while...
| Identifer | oai:union.ndltd.org:nusl.cz/oai:invenio.nusl.cz:364223 |
| Date | January 2017 |
| Creators | Kalčic, Filip |
| Contributors | Janeba, Zlatko, Dvořák, Dalimil |
| Source Sets | Czech ETDs |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/masterThesis |
| Rights | info:eu-repo/semantics/restrictedAccess |
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