DESIGN AND SYNTHESIS OF ELLIPTICINIUM SALTS AND 1,2-DIHYDROELLIPTICINES WITH HIGH SELECTIVITIES AGAINST HUMAN CNS CANCERS IN-VITRO

9-Methoxy-2-methylellipticinium acetate (6), along with the 9-methyl a nd 9-chloro derivatives (7, and 8, respectively) have shown remarkable selectivities in vitro against the NCI human CNS cancer subpanel. In order to target these types of compounds to the CNS in vivo, a series of 1,2-dihydroellipticines was synthesized. 9-Methoxy-2-methyl-1,2-dih ydroellipticine (9) retained the potency and selectivity of the parent compound 6 but was unstable toward oxidation to 6. In order to improv e the stability of 9, it was converted to the vinylogous amide 33 by i ntroduction of a formyl group in the 4-position. Compound 33 proved to be much more stable than 9, but it was also less potent than 9 by abo ut 1 order of magnitude, and it was less selective for the CNS subpane l than 9. To overcome the limited water solubilities of the ellipticin es and dihydroellipticines, several ellipticine analogues incorporatin g polar groups on the N-2 nitrogen were prepared. The 2-(methoxymethyl )ellipticinium salts 24 and 25, as well as the (methylthio)methyl cong ener 26, were relatively potent anticancer agents which displayed cyto toxicity selectivity profiles similar to compound 6. The cytotoxic dih ydroellipticines 9 and 10 exhibited potencies approaching that of elli pticine itself in facilitating the formation of a ''cleavable complex' ', while the least cytotoxic ellipticine derivatives exhibited no clea vage above background.