Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines

New synthetic routes to a series of tetra- and pentacyclic acridines relate d in structure to marine natural products are reported. The novel water-sol uble agent dihydroindolizino[7,6,5-kL]acridinium chloride 14 has inhibitory activity in a panel of non-small-cell lung and breast tumor cell lines exc eeding that of m-AMSA. The salt inhibited the release of minicircle product s of kDNA confirming that disorganization of topoisomerase II partly underl ies the activity of the compound. COMPARE analysis of the NCI mean graph pr ofile of compound 14 at the GI(50) level corroborates this conclusion with Pearson correlation coefficients (>0.6) to clinical agents of the topoisome rase II class: however, this correlation was not seen at the LC50 level. Th e inhibitory action of 14 on Saccharomyces cerevisiae transfected with huma n topoisomerase II isoforms showed a 3-fold selectivity against the II alph a isoform over the II beta isoform. Unlike nt-AMSA, 14 is not susceptible t o P-glycoprotein-mediated drug efflux and retains activity in lung cells wi th derived resistance to the topoisomerase II inhibitor etoposide.