REDOX CYCLING OF O-NAPHTHOQUINONES IN TRYPANOSOMATIDS - SUPEROXIDE AND HYDROGEN-PEROXIDE PRODUCTION

beta-Lapachone and structurally related lipophilic o-naphthoquinones, namely, CG 8-935, CG 9-442, CG 10-248 and mansonones A, C, E, and F, w ere investigated for redox cycling, production of reactive oxygen spec ies, and cytotoxicity in the trypanosomatids Crithidia fasciculata and Leptomonas seymouri. Structural analysis of the assayed quinones indi cated that a tricyclic structure, including a naphthalene ring, a 1,2b or 1,8bc pyran ring, and two ortho-carbonyl groups were required for quinone activities. The contribution of oxygen radical production to q uinone cytotoxicity was supported by: (a) spectroscopic observation of quinone redox cycling; (b) production of the semiquinone radical; (c) H,O, and O-2(-) production; (d) the effect of beta-lapachone on thiol pools in C. fasciculata; (e) the effect of quinones on cell respirati on; (f) superoxide dismutase inactivation after incubation of C. fasci culata with CG 8-935; and (g) the effect of quinones on cell growth. C opyright (C) 1996 Elsevier Science Inc.