Synthesis of anti-angiogenetic natural-like acylphloroglucinols and selective ABC transporter modulators

The first part of the thesis (chapter 1 and 2) deals with natural or natural-like phenols with anti-angiogenic property. Chapter 1 reviews recent reports of anti-angiogenic natural phenolic compounds specifically addressing their chemistry, synthesis and possible structure modifications. Thirteen representatives of eight different natural or natural-like phenolic subclasses with significant anti-angiogenic activity are presented. Whenever available, structure-activity relationship is also discussed. In chapter 2, we describe a synthetic approach for natural and natural-like acylphloroglucinols with anti-proliferative, anti-oxidative and tube-formation inhibitory activity. Two series of mono- and bicyclic acylphloroglucinols derived from secondary metabolites in the genus Hypericum (Hypericaceae) were synthesised and tested in vitro for anti-proliferative and tube-formation inhibitory activity in human microvascular endothelial cells (HMEC-1). In addition, their anti-oxidative activity was determined via an ORAC-assay. Our experiments show simpler acylphloroglucinols containing simpler substitution patterns than hyperforin can show good anti-proliferative effects and remarkable tube formation inhibition. The second part of the thesis (chapter 3 and 4) reports the synthesis and bioactive evaluation of compounds aiming to selectively inhibit ABCC1 and ABCG2 transporter, respectively. In chapter 3, a series of flavonoids were synthesised and characterized in cellular assays for modulation of the ABC transporters-ABCC1 (MDCKII-MRP1 cells), ABCB1 (Kb-V1 cells) and ABCG2 (MCF-7/Topo cells). The most potent ABCC1 modulators identified among these flavonoid-type compounds were comparable to reversan regarding their potency, but superior in terms of selectivity over ABCB1 and ABCG2. In chapter 4, we report synthesis of quinoline analogues targeting breast cancer resistance protein derived from tariquidar. All tested compounds show weak or no inhibitory activity over ABCB1 and ABCC1 transporter but good inhibitory activity towards ABCG2. However, compared with our reference indole compounds, the replacement of anilide core by quinoline moiety gave less potent compounds. The introduction of amine groups on the tetrahydroisoquinoline moiety can increase the water solubility to some extent, but the poor water solubility is still the main problem for this series of compounds. In chapter 5, photo-rearrangement and methanol addition of aryl chalcones to 1-propanones in the presence of triphenylphosphine is reported. We propose two possible mechanistic hypotheses for the rearrangement/addition reaction. To further demonstrate the applicability of the reaction, we applied it to synthesis of 2-substituted terminal enones