Ellipticine is a natural product possessing multimodal cytotoxic activity including DNA intercalation, topoisomerase II inhibition, c-Kit kinase inhibition and restoration of function to mutant p53 protein.¹ While ellipticine itself is not a suitable candidate for therapeutic use, derivatives including 2-methyl-9-hydroxyellipticinium acetate and 2-(2-(diethylamino)ethyl)-9-hydroxyellipticinium chloride, have progressed to clinical trials.² 

The effect of derivatisation on the isoellipticine is uncharted and structural diversification of isoellipticine could lead to drug candidates with a better clinical profile due to enhanced target specificity. Our initial approach to this uses substitutent modification at positions 10, 7 and 2 (salt formation at the N2 position represents a favourable attribute for cytotoxic activity as illustrated by the two most successful ellipticines). A number of novel derivatives of isoellipticine have been synthesised and further derivatised. Preliminary biological testing of novel compounds was performed using a topoisomerase II decatenation assay and via assessment of the anticancer profile using the National Cancer Institute 60 cell line screen for cellular activity.³

We will present here the design, synthesis and  anticancer properties and significant cell line selectivity of a series of novel ellipticine derivatives devised in our laboratory.

References

1. E.C. O’Sullivan, C.M. Miller, F.M. Deane and F.O. McCarthy. Stud. Nat. Prod. Chem. Emerging targets in the bioactivity of Ellipticines and derivatives, 2013, 39(6), 189.
2. C.M. Miller and F.O. McCarthy, RSC Adv. Isolation, biological activity and synthesis of the natural product ellipticine and related pyridocarbazoles, 2012, 2(24), 8883.
3. C.M. Miller, E.C. O'Sullivan, K.J. Devine and F.O. McCarthy, Org. Biomol. Chem. Synthesis and Biological Evaluation of Novel Isoellipticine Derivatives and Salts, 2012, 10(39), 7912.