The absorption characteristics and acid dissociation constants of the semiquinone radicals of several methyl derivatives of benzoquinone and naphthoquinone have been determined by pulse radiolysis.Absolute rate constants for electron transfer from the superoxide-ion 0; to mono-and di-methyl benzoquinones have been determined. In the case of duroquinone, evidence has been obtained for the occurrence of the equilibrium reaction :with Kc = 2.3 _+ 0.2 x

؉ and radical-addition, [RSO 2 ⅐⅐⅐␤-carotene] ⅐ in an approximate 3:1 ratio. The ␤-carotene radical-cation and adduct-radicals are highly resonance stabilized and undergo slow bimolecular decay to non-radical products. These carotenoidderived radicals react differently with oxygen, a factor which is expected to influence the antioxidant activity of ␤-carotene within tissues of varying oxygen tension in vivo.

No abstract

Superoxide anion reacts with hyp~hlorous acid to yield free hydroxyl radicals, as shown by the hydroxylation of benzoate. This reaction is analogous to the Haber-Weiss reaction but in the absence of metal ions is at least six orders of magnitude faster.

A series of 2-cycloalkyl- and 2-alkyl-3-(hydroxymethyl)-1-methylindoloquinones and corresponding carbamates have been synthesized and substituted in the 5-position with a variety of substituted and unsubstituted aziridines. Cytotoxicity against hypoxic cells in vitro was dependent upon the presence of a 5-aziridinyl or a substituted aziridinyl substituent for 3-hydroxymethyl analogues. The activity of 5-methoxy derivatives was dependent upon the presence of a 3-(carbamoyloxy)methyl substituent. Increasing the steric bulk at the 2-position reduced the compounds' effectiveness against hypoxic cells. A 2-cyclopropyl substituent was up to 2 orders of magnitude more effective than a 2-isopropyl substituent, suggesting possible radical ring-opening reactions contributing to toxicity. Nonfused 2-cyclopropylmitosenes were more effective than related fused cyclopropamitosenes reported previously. The reduction potentials of the quinone/semiquinone one-electron couples were in the range -286 to -380 mV. The semiquinone radicals reacted with oxygen with rate constants 2-8 x 10(8) dm3 mol-1 s-1. The involvement of the two-electron reduced hydroquinone in the mediation of cytotoxicity is implicated. The most effective compounds in vitro were the 2-cyclopropyl and 5-(2-methylaziridinyl) derivatives, and of these, 5-(aziridin-1-yl)-2-cyclopropyl-3-(hydroxymethyl)-1-methylindole-4 ,7-dione (21) and 3-(hydroxymethyl)-5-(2-methylaziridin-1-yl)-1,2-dimethylindole+ ++-4,7-dione (54) were evaluated in vivo. Both compounds showed antitumor activity both as single agents and in combination with radiation, with some substantial improvements over EO9 (3) at maximum tolerated doses and as single agents against the RIF-1 tumor model and comparable efficacy in the KHT tumor model.