Electrochemical Reductive Activation of Mitomycin C

Article abstract of DOI:10.1021/ja00274a052

We have used the electrochemical techniques of cyclic voltammetry and preparative flow cell electrolysis to study the role of one-electron vs. two-electron transfer in the reductive activation of mitomycin C (MC) and a primary mitosene metabolite, 1,2-cis-2,7-diamino-1-hydroxymitosene (6), to reactive intermediates in polar aprotic solvents.Cyclic voltammetry of MC in DMF (0.1 M TEAP) showed that MC undergoes two quasi-reversible electron-transfer processes at -0.937 and -1.410 V vs.Ag/AgCl, saturated KCl.A following chemical reaction appeared to occur after transfer of a second electron at -1.410 V as indicated by an anodic wave at -0.710 V and a cathodic wave at -0.800 V that appeared upon multicycle scanning.Flow cell reduction at -0.950 V vs.Ag/AgCl, 3 M NaCl over graphite, formed the radical anion of MC in DMF or Me2SO as characterized by EPR (g=2.0045).When the radical anion of MC in DMF was mixed with water, parent MC and at least eight other products were generated as detected by HPLC.The one-electron-reduction product profiles showed a pH dependence.Flow cell reduction of MC at -1.450 V formed the dianion of MC in DMF or Me2SO, which generated only two products when mixed with water.These products have been identified by mass spectral and NMR analyses to be 10-decarbamoyl-2,7-diaminomitosene (14) and 2,7-diamino-2,3-dihydro-6-methyl-1H-pyrrolo<1,2-a>indole-5,8-dione (22).Generation of 22 was completely suppressed when the dianion was added to phosphate buffer.Flow cell reduction of 6 in DMF at -1.200 or -1.500 V generated the radical anion (g=2.0045) or dianion, respectively.These species both gave 1,2-cis-2,7-diamino-2,3-dihydro-6,9-dimethyl-1-hydroxy-1H-pyrrolo<1,2-a>indole-5,8-dione (27) as the sole product when mixed with water.These data provide evidence that one-electron reduction is sufficient to activate MC and its primary metabolites to reactive intermediates.Furthermore, the results suggest that one-electron transfer is the dominant mode of bioreductive activation since the HPLC profile of the radical-anion-generated products of MC closely resembled the profile of metabolites generated from reduction with purified flavoenzymes.