SYNTHESIS AND ANTITUMOR PROPERTIES OF N-[2-(DIMETHYLAMINO)ETHYL]CARBOXAMIDE DERIVATIVES OF FUSED TETRACYCLIC QUINOLINES AND QUINOXALINES - A NEW CLASS OF PUTATIVE TOPOISOMERASE INHIBITORS

A series of tetracyclic quinoline- and quinoxalinecarboxamides were pr epared, and their cytotoxicities were evaluated in a series of murine human tumor cell lines. Most, of the quinoline derivatives were prepar ed by an adaptation of the Pfitzinger synthesis, followed by thermal d ecarboxylation and coupling with N,N-dimiethylethylenediamine via a mi xed anhydride method using isobutyl chloroformate, The quinoline analo gues showed cytotoxicities broadly similar to those of the known tricy clic acridine-4-carboxamide mixed topoI/II inhibitor DACA, with thieno and indeno analogues being the most active. They showed little decrea se in potencies against the Jurkat human leukemia topo II-resistant li nes JL(A) and JL(C), suggesting their cytoxicity does not result prima rily from inhibition of topo II. The quinoxaline analogues had more va ried IC50 values, being on average less cytotoxic than the quinoline d erivatives, but appeared to have a similar mode of action. Overall, th is new class of compounds appear to be mixed topo I/II inhibitors, up to 3-fold more cytotoxic than DACA in the human leukemia cell lines st udied, with in vivo activity in colon 38 comparable to that of DACA an d doxorubicin.