Sigmatropic reactions of the aziridinyl semiquinone species. Why aziridinyl benzoquinones are metabolically more stable than aziridinyl indoloquinones

Described herein is the chemistry of aziridinyl semiquinone species, which are formed upon one-electron metabolic reduction of aziridinyl quinone anti tumor agents. The semiquinone species undergo a type of electrocyclic react ion known as a 1,5-sigmatropic shift of hydrogen. This reaction converts th e aziridinyl group to both ethylamino and amino groups resulting in a loss of cytotoxicity. Since the radical anion conjugate base does not undergo ri ng opening as fast as the semiquinone, it was possible to determine the sem iquinone pK(a) values by plotting the percent sigmatropic products versus p H. Aziridinyl quinones based on benzoquinones, such as DZQ and AZQ, possess semiquinone pK(a) values below neutrality. In contrast, an indole-based az iridinyl quinone possesses a semiquinone pK(a) value of 9.3. Single electro n reduction of DZQ and AZQ by NADPH: cytochrome P-450 reductase at physiolo gical pH therefore affords the radical anion without any sigmatropic rearra ngement products. In contrast, the same reduction of an aziridinyl indoloqu inone affords the semiquinone which is rapidly converted to sigmatropic rea rrangement products. These findings suggest that aziridinyl quinone antitum or agents based on indoles will be rapidly inactivated by one electron-redu ctive metabolism. A noteworthy example is the indoloquinone agent EO9, whic h is rapidly metabolized in vivo. In contrast, benzoquinone-based aziridiny l quinone antitumor agents such as AZQ, DZQ, and the new benzoquinone analo gue RH1 do not suffer from this problem.