HYPOXIA-SELECTIVE ANTITUMOR AGENTS .13. EFFECTS OF ACRIDINE SUBSTITUTION ON THE HYPOXIA-SELECTIVE CYTOTOXICITY AND METABOLIC REDUCTION OF THE BIS-BIOREDUCTIVE AGENT NITRACRINE N-OXIDE

A series of nuclear-substituted derivatives of nitracrine N-oxide (2; a bis-bioreductive hypoxia-selective cytotoxin) were prepared and eval uated, seeking analogues of lower nitroacridine reduction potential. D isubstitution with Me or OMe groups at the 4- and 5-positions did not provide analogues with one-electron reduction potentials significantly lower than those of the corresponding monosubstituted derivatives (E( 1) ca. -350 mV for both the 4-OMe and 4,5-diOMe compounds). This appea rs not to be due to a concomitant raising of the acridine pK(a), but t o a lack of direct electronic effect of substituents in the ring not b earing the nitro group. Conversely, placing two OMe groups in the nitr o-bearing ring does result in a substantial further lowering of reduct ion potential (the 2,4-diOMe analogue has an E(1) of -401 mV). The mon o- and disubstituted N-oxides have substantially lower cytotoxicities than the parent nitracrine N-oxide 2 but generally retain very high hy poxic selectivity. The OMe-substituted N-oxides all showed greater met abolic stability than 2 in hypoxic AA8 cell cultures, and the 4-OMe co mpound 6 had improved activity in EMT6 multicellular spheroids suggest ing that this metabolic stabilization may-allow more efficient diffusi on-in tumor tissue. The parent compound 2 was selectively toxic to hyp oxic cells in KHT tumors in vivo and clearly superior to nitracrine it self (although only at doses which would eventually be lethal to the h ost). The analogues of lower E(1), including 6, were not superior to 2 in vivo, indicating that metabolic stabilization of the nitro group i s not alone sufficient to improve therapeutic utility.