title: Sigmatropic reactions of the aziridinyl semiquinone species. Why aziridinyl benzoquinones are metabolically more stable than aziridinyl indoloquinones.
abstract: Described herein is the chemistry of aziridinyl semiquinone species, which are formed upon one-electron metabolic reduction of aziridinyl quinone antitumor agents. The semiquinone species undergo a type of electrocyclic reaction known as a 1,5-sigmatropic shift of hydrogen. This reaction converts the aziridinyl group to both ethylamino and amino groups resulting in a loss of cytotoxicity. Since the radical anion conjugate base does not undergo ring opening as fast as the semiquinone, it was possible to determine the semiquinone pK(a) values by plotting the percent sigmatropic products versus pH. Aziridinyl quinones based on benzoquinones, such as DZQ and AZQ, possess semiquinone pK(a) values below neutrality. In contrast, an indole-based aziridinyl quinone possesses a semiquinone pK(a) value of 9.3. Single electron reduction of DZQ and AZQ by NADPH: cytochrome P-450 reductase at physiological pH therefore affords the radical anion without any sigmatropic rearrangement products. In contrast, the same reduction of an aziridinyl indoloquinone affords the semiquinone which is rapidly converted to sigmatropic rearrangement products. These findings suggest that aziridinyl quinone antitumor agents based on indoles will be rapidly inactivated by one electron-reductive metabolism. A noteworthy example is the indoloquinone agent EO9, which is rapidly metabolized in vivo. In contrast, benzoquinone-based aziridinyl quinone antitumor agents such as AZQ, DZQ, and the new benzoquinone analogue RH1 do not suffer from this problem.
authors.affiliation: Department of Chemistry and Biochemistry, Box 871604, Arizona State University, Tempe, Arizona 85287-1604, USA.
authors.forename: C
authors.initials: C
authors.lastname: Xing
authors.forename: E B
authors.initials: EB
authors.lastname: Skibo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D001388:Aziridines / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry; D016227:Benzoquinones / Q000737:chemistry*; D002384:Catalysis; D004355:Drug Stability; D004579:Electron Transport; D006859:Hydrogen; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007536:Isomerism; D010084:Oxidation-Reduction; D011522:Protons; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D001562:Benzimidazoles; D016227:Benzoquinones; D011522:Protons; C025232:semiquinone radicals; D006859:Hydrogen