Design, synthesis and biological evaluation of the 2-morpholinobenzoic acids and phenylimidazo[1-2a]quinolines as novel classes of anti-proliferative compounds

Abstract

Cancer is a collection of diseases characterised by the uncontrolled proliferation of mutated cells that spread around the body affecting organ function, eventually leading to death. Due to the current ageing population, cancer is the second leading cause of global deaths, making research into potent and selective treatments for this disease extremely valuable. In this study, two classes of novel anti-cancer compounds were investigated; the 2-morpholinobenzoic acids and the 2-phenylimidazo[1,2-a]quinolines (PIQ’s), with the aim of optimising the biological activity of these anti-cancer molecules. The 2-morpholinobenzoic acids target phosphatidylcholine-specific phospholipase C (PCPLC), a regulatory enzyme associated with cancer development and metastasis in various cancer cell lines. 2-Morpholinobenzoic acids have been shown to have improved PC-PLCBC inhibitory activity compared to the current literature standard, D609. Following a preliminary molecular docking study, 141 2-morpholinobenzoic acid analogues were synthesised across three major series and evaluated for PC-PLCBC inhibition and anti-proliferative activity. It was found that the original 2-morpholinobenzoic acids were optimal at inhibiting PC-PLCBC, whilst analogues containing hydroxamic acids had the best anti-proliferative activity. Additionally, the 2-morpholino group and 5-N-benzyl group were found to be essential for activity. Furthermore, 2-morpholinobenzoic acid derivatives with additional with nitric oxide (NO) donating groups exhibited significantly improved anti-proliferative activity, substantiating a literary link between PC-PLC and NO. Lastly, a photo-affinity probe was synthesised and found to still inhibit PC-PLCBC at levels previously deemed significant and therefore may have future use for the isolation of human PC-PLC. The PIQ compounds target the CYP1 enzymes, a family of enzymes shown to drive cancer development through metabolising pro-carcinogenic xenobiotics into their mutagenic forms, as well as being implicated in propagating neoplasia and resistance to various chemotherapies. Lead compound 53a exhibited selective CYP1 inhibition and potent anti-proliferative activity. To further explore these compounds, 24 PIQ analogues were synthesised, with all compounds bearing imidazole substituents demonstrating significantly lower anti-proliferative activity than 53a. Pleasingly, the 2,3-napthalene analogue 67a was able to impart a higher degree of proliferation arrest than 53a, in addition to a sub-micromolar IC50 concentration, setting a new benchmark for the PIQ compounds.