Ellipticine and related anticancer agents

Ellipticine (E), 9-methoxyellipticine (9ME) and olivacine are antitumour alkaloids isolated from Ochrosia elliptica and Aspidosperma olivaceum. 9-Hydroxyellipticine (9HE), a metabolite of 9ME, exhibits higher potency than E, but water insolubility has hampered its progression to clinical trials. A number of water soluble derivatives with, for example, a quaternary ammonium ion at position 2 or an amino-alkyl substituent at position 1, have been synthesised to overcome this problem. Elliptinium (2-methyl-9HE), datelliptium (2(diethylamino)ethyl-9HE), retelliptine (1-diethyl-aminopropylamino-9ME; BD-84), pazellipticine (1-diethylamino-propylamino-9-aza-OL; BD-40), elliprabin (e-arabinosyl-SHE), RPI-6 (carbamate at position 5 of E) and S-16020 (1-diethylaminoethylolivacine) have been extensively studied. Among these, elliptinium and datelliptium have been used for treatment of advanced breast cancer. Ellipticine analogues intercalate with DNA and show inhibition of topoisomerase II, as well as ditercalinium (a bispyridocarbazole derivative) and intoplicine (a 7H-benzo[e]pyrido[4,3-b] indole derivative). 9HE, in addition to inhibiting of topoisomerase II, is able to inhibit kinases which phosphorylate mutant p53 protein, a tumour suppressor gene product. The resulting high amount of dephosphorylated mutant p53 strongly induces expression of an apoptosis-inducing gene, bax. The compounds substituted with quaternary ammonium lose the ability to inhibit phosphorylation of p53. T-215 (9-pentanediolate-ellipticine), a derivative of 9HE, has been developed as the first drug which induces apoptosis of cancer cells selectively, via inhibition of phosphorylation of mutant p53.