ANTICANCER SPECIFICITY OF SOME ELLIPTICINIUM SALTS AGAINST HUMAN BRAIN-TUMORS IN-VITRO

Novel structure-activity relationships (SAR) distinct from known SAR f or ellipticines have been revealed for certain ellipticinium salts. In particular, ellipticiniums such as the prototypical 9-methoxy-2-methy lellipticinium (I- or OAc-) were found to be preferentially cytotoxic to the brain tumor cell line subpanel of the NCI 60 cell-line screenin g panel. Similar specificity also was apparent with 9-unsubstituted el lipticiniums, or others bearing 9-methyl or 9-chloro substituents. In contrast, 9-hydroxy-substituted ellipticiniums, as well as all nonquat ernized ellipticines tested, were devoid of brain tumor specificity. T herefore, it did not appear that this unusual preference was correlate d with the relative availability of redox cycling mechanisms, since re dox cycling presumably is blocked in 9-methyl- and 9-chloroellipticini ums. Indeed, related investigations have indicated that the brain tumo r specificity is mediated by preferential uptake and intracellular acc umulation of the specific ellipticiniums. The present study further su pports that the NCI in vitro ''disease-oriented'' primary screen can f acilitate the discovery of novel, selectively cytotoxic leads for in v ivo and mechanistic investigations.