Paraquat has been found to accept electrons from nitric oxide synthase (NOS) whereupon the reduced paraquat generates toxic O.sub.2.sup.- and prevents NOS from giving electrons to arginine and thereby inhibits NO production. This is generalized for compounds with a redox potential greater than nitric oxide synthase. The compounds inhibit nitric oxide synthase and kill cells including NOS by generating O.sub.2.sup.- and also by depriving the cells of the NO which they need. Applications include treating paraquat-induced injury and pathologically proliferating cells (tumors, restenosis benign prostatic hypertrophy, pulmonary hypertension, infective pathogens).

Duke University

National Jewish Medical and Research Center

Cornell Research Foundation, Inc.

Treatments based on discovery that nitric oxide synthase is a paraquat diaphorase

Yungamycin A has been demonstrated to have unexpected in vivo anticancer activity. New compounds Yungamycin B and C are also disclosed, and have been demonstrated to be specific for DT-diaphorase, as well as to have in vivo anticancer activity.

Arizona Board of Regents acting for and on behalf of Arizona State University

Treatment of neoplasms with yujungamycins

The merits of N-unsubstituted indoles and cyclopent[b]indoles as DNA-directed reductive alkylating agents are described. These systems represent a significant departure from N-substituted and pyrrolo[1,2-.alpha.] fused systems such as the mitomycins and mitosenes. The cyclopent[b]indole-based aziridinylquinone, when bearing an acetate leaving group, was found to be cytotoxic and displayed significant in vivo activity against syngeneic tumor implants. This particular analogue was unexpectedly superior to the others studied, both in terms of high specificity for the activating enzyme DT-diaphorase and in high % DNA alkylation. Alkylation by a quinone methide intermediate as well as by the aziridinyl group were examined for crosslinking. The possible metabolites of the most active indole species were prepared and found to retain cytotoxicity, strongly suggesting that in vivo activity could also be sustained. The indole systems in the present invention display selectivity for melanoma and for non small cell lung, colon, renal, and prostate cancers when administered in an effective amount. The cancer specificity observed is believed to pertain to differential substrate specificity for DT-diaphorase.

diaphorase/neoplasms

Treatments based on discovery that nitric oxide synthase is a paraquat diaphorase

Treatment of neoplasms with yujungamycins

Cytotoxic N-unsubstituted indoles and cyclopent(B)indoles and method of making and using same

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