Abstract/Summary

The key role of angiogenesis in the growth and metastasis of cancer has led to the inclusion of antiangiogenic therapy in cancer treatments, which has proved clinically beneficial when combined with cytotoxic effects in a multi-targeting approach (e.g. sunitinib is first line therapy for renal cancer). However, current multi-targeting therapies (administered as drug combinations or single drug) suffer from increased adverse events. Flavonoids present advantageous polypharmacological anticancer properties and are well tolerated. Hence, this study explores the bi-modal antiangiogenic and cytotoxic efficacy of a group of synthetic flavonoids as potential anticancer agents. First, reported data on the antiangiogenic activities of flavonoids was analyzed via systematic and quantitative analyses, establishing their antiangiogenic effectiveness. Antiangiogenic structure activity relationship (SAR) data was extracted from the conducted analysis. Cytotoxic SARs were gathered from reported studies and combined with the antiangiogenic SAR, resulting in the design of two sets of 5,7/7,8-disubstituted-4’-chloro/bromophenyl flavones (Chapter 2). The designed flavones (7-14) were synthesized and spectroscopically characterized with good yields (60-97%) and purities (>90%). Compounds 9, 11, 12 and 14 particularly showed significant in vitro angiogenic inhibition against endothelial cell (EC) vascular endothelial growth factor (VEGF)-induced tube formation and migration (>50% and 25-37%, respectively, at 10 μM). The 4-thio derivatives 11 and 12 inhibited VEGFR2 phosphorylation (57 and 37% at 10 μM, respectively) in western blotting and were oriented in a favorable position inside its ATP binding site in a molecular docking study (Chapter 3). Further optimization of the test compounds was investigated through ruthenium (Ru) or iridium (Ir) metal complexation based on their reported antiangiogenic/cytotoxic effectiveness. The novel Ru(II)-p-cymene complexes (19 and 20) of flavones 11 and 13 were successfully synthesized and spectroscopically confirmed with 46 and 30% yields, respectively (Chapter 4). The bi-modal anticancer effects of 11 and 13 in addition to the impact of Ru complexation on the measured effects were evaluated in vitro (Chapter 5). The lead thioflavone 11 displayed strong cytotoxic (IC50=1.2 ± 0.8 and 43.06 ± 1.29 µM on MCF-7 and MDA-MB-231, respectively) and antimigratory activities (43% inhibition at 1 µM on MDA-MB-231) on breast cancer cells, in addition to the notable antiangiogenic effects on EC (e.g. 42% tube formation inhibition at 1 µM). These effects were comparable to reported values for the drug sunitinib in the same assays (e.g. IC50=5 µM on MCF-7, 50% tube formation inhibition at 10 µM). Complexation with Ru negatively impacted the tube formation inhibitory effects of 11 and 13. Ru chelation diminished 11’s cytotoxicity against MCF-7 and MDA-MB-231 breast cancer cells whereas the antimigratory activity against MDA-MB-231 was equivalent to the parent flavone. In contrast, Ru complexation enhanced the cytotoxic and antimigratory effects of the oxoflavone 13 against breast cancer cells (e.g. 50 versus 33% inhibition of MCF-7 migration, p<0.05). Finally, the test derivatives showed a presumably non-intercalative binding with VEGF and c-myc i-motif DNA, as novel anticancer targets, in UV-Vis spectroscopic studies (Chapter 5). This work identified compound 11 as a promising anticancer agent with dual antiangiogenic and cytotoxic activities. Its structural features and interaction with the VEGF/VEGFR2 pathway provides a suitable base for extension towards novel anticancer applications in the future, such as the development of dual antiangiogenic and immunomodulatory agents (Chapter 6).