Heterocycles to block the cell cycle : novel ellipticines and their anticancer effects

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. 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. 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. 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.


Graphical Abstract
Heterocycles to block the cell cycle: novel ellipticines and their anticancer effects

Abstract:
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.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.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.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. Five different orientations of 9-hydroxyellipticine 2 were investigated.

Ellipticine
 Two nanoseconds of molecular dynamics were performed for each complex.
 New binding mode proposed.

Figure 4 .Figure 5 . 7 -
Figure 4. 5 μM 7-hydroxyisoellipticine causes a G2/M cell cycle arrest in a number of leukaemia cell lines The cell cycle of leukaemia cells incubated with 5 μM 7-hydroxyisoellipticine or 0.5% DMSO control for 24 hours was analyzed by propidium iodide staining of nuclei and flow cytometry.Values represent the percentage (%) of cells in each cell cycle phase of the cells treated with 7-hydroxyisoellipticine. Black line = 5 μM 7-hydroxyisoellipticine, grey = 0.5 % DMSO control.