title: Biological evaluation of halogenated flavone derivatives as antiangiogenic and anticancer agents
Creators: name: Khater, Mai
Publisher: name: University of Reading
Year: 2025

description: 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 
(&gt;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 (&gt;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&lt;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).