2-CYCLOPROPYLINDOLOQUINONES AND THEIR ANALOGS AS BIOREDUCTIVELY ACTIVATED ANTITUMOR AGENTS - STRUCTURE-ACTIVITY IN-VITRO AND EFFICACY IN-VIVO

A series of 2-cycloalkyl- and 2-alkyl-3-(hydroxymethyl)-1-methylindolo quinones and corresponding carbamates have been synthesized and substi tuted in the 5-position with a variety of substituted and unsubstitute d aziridines. Cytotoxicity against hypoxic cells in vitro was dependen t upon the presence of a 5-aziridinyl or a substituted aziridinyl subs tituent for 3-hydroxymethyl analogues. The activity of 5-methoxy deriv atives was dependent upon the presence of a 3-(carbamayloxy)methyl sub stituent. Increasing the steric bulk at the 2-position reduced the com pounds' effectiveness against hypoxic cells. A 2-cyclopropyl substitue nt was up to 2 orders of magnitude more effective than a 2-isopropyl s ubstituent, suggesting possible radical ring-opening reactions contrib uting to toxicity. Nonfused 2-cyclopropylmitosenes were more effective than related fused cyclopropamitosenes reported previously. The reduc tion potentials of the quinone/semiquinone one-electron couples were i n the range -286 to -380 mV. The semiquinone radicals reacted with oxy gen with rate constants 2-8 x 10(8) dm(3) mol(-1) s(-1). The involveme nt of the two-electron reduced hydroquinone in the mediation of cytoto xicity is Implicated. The most effective compounds in vitro were the 2 -cyclopropyl and 5-(2-methylaziridinyl) derivatives, and of these, pro pyl-3-(hydroxylindole)-1-methylindole-4,7-dione (21) and -methylazirid in-1-yl)-1,2-dimethylindole-4,7-dione (54) were evaluated in vivo. Bot h compounds showed antitumor activity both as single agents and in com bination with radiation, with some substantial improvements over EO9 ( 3) at maximum tolerated doses and as single agents against the RIF-1 t umor model and comparable efficacy in the KHT tumor model.