Synthesis and Biological Evaluation of Chalcone Scaffolds as Potential Antiangiogenic Agents.
Angiogenesis is an integral part of tumour growth and development. Endothelial cell proliferation, migration and differentiation are the main hallmarks of this physiological process. From this, the use of antiangiogenic therapy have brought about a range of licensed FDA approved agents (that are also used by the NHS), that aim to regress tumour induced angiogenesis. However, issues such as: drug resistance, evasion and poor efficacy have limited the use of antiangiogenic therapy as a main stake in anti-cancer therapy. The need for multi-targeted or combinatorial therapies are ever more needed to enhance the current use of these drugs. Therefore, in an attempt to identify novel compounds that exhibit antiangiogenic activity, a group of 1-3-diphenylpropenones (chalcones) were designed, synthesised and biologically evaluated using AH1 (2-chloro-2’5’-dihydroxychalcone) as the parent compound. Methods: Chalcones were synthesised using variations of the Clasien-Schmidt condensation reaction, to develop a compound library based on AH1 (the parent compound). Thereafter, using HUVECs as an angiogenesis model, the effects of the compounds on HUVEC proliferation and migration were evaluated. This was carried out using the MTT cell proliferation assay and the wound healing “scratch” assay. Therein mechanistic evaluation was carried via gel electrophoresis and chemiluminescence western blot. Main findings: Structure activity relationships (SARs) studies identified, that novel compounds AH9 (2-bromo-2’5’-dihydroxychalcone) and AH12 (2-nitro-2’5’-dihydroxychalcone) were shown to exhibit strong anti-proliferative activity along with AH1. Other synthesised derivatives containing different functional groups such as, alkoxy, halogen and methyl did not exhibit similar activities to AH1. The culmination of structure activity relationship suggested that 2’5’-dihydroxy moiety was important to the observed activity only in conjunction with 2-chloro or now 2-bromo substitution on the other phenyl ring. Due to AH9’s better drug likeness over AH12, AH9 and AH1 were taken forward as the lead candidates. Anti-migratory analysis of lead candidates and licensed drug Sorafenib were conducted against HUVECs. AH9 (p < 0.0007) was shown to exhibit significantly more potent inhibitory effects on endothelial migration than AH1 (p = 0.19) and Sorafenib (p = 0.41) over the 8 hour time course study when compared to the untreated control. Mechanistic evaluation identified that AH9 could be exerting its anti-proliferative and potent anti-migratory activity via inhibiting ERK kinase phosphorylation, this was seen at 10μM (p < 0.0001). Discussion and conclusion: To summarise, anti-proliferative and potent anti-migratory activity, towards HUVECs, of a novel molecule AH9 have been identified showing significant effects against two hallmarks of the angiogenesis cascade. AH9 presents a strong case as an agent capable of being developed as an angiogenesis inhibitor for anti-angiogenic therapy.
- PhD