Synthesis and evaluation of novel ellipticine salt derivatives as anticancer agents

Cancer is the second leading cause of death worldwide, killing an estimated 1 in 6 people. Ellipticine (1) is a natural product which has potent anticancer activity and has been subject to extensive study since its discovery, in 1959, with the key aim of identifying derivatives with clinical application.

Functionalisation of the ellipticine pharmacophore is key to developing potent and selective analogues. For example, generation of quaternary ellipticine salts, helps to overcome issues surrounding solubility and can improve selectivity whereas the most potent anticancer ellipticine derivatives have a hydroxyl or methoxy substituent at the 9-position. This work outlines the synthesis of quaternary ellipticine salts and their subsequent biological evaluation. Alkyl groups were introduced at the 6-position, as well as formyl or hydroxy groups at the 9-position, as these substituents have been previously shown to improve activity.

Biological evaluation encompassed measurement of growth inhibition against twelve cancer cell lines and submission to the NCI 60 Cell Lines Screen. Substitution at the 9-position greatly improved activity, while increasing substituent size at the 6-position led to lower potency. A number of potent derivatives have been identified following biological evaluation, with long chain alkyl salts displaying sub-micromolar average GI₅₀ values.