92761-60-9Relevant articles and documents
Studies on the Use of Cr(ClO4)2 for the Reductive Activation of Mitomycin C 1
Hong,Kohn, Harold
, p. 4634 - 4644 (2007/10/02)
Cr(ClO4)2 has been shown to be a highly efficient reductant of the anticancer agent, mitomycin C (1). Two different Cr(ClO4)2-mediated reductive techniques were developed and utilized in buffered water and methanolic solutions. In the first procedure, Cr(ClO4)2 (1-2 equiv) was directly added to 1 at various "pH" values. Key observations included the following: (1) Consumption of mitomycin C was rapid and generated as the major products trans- and cis-10-decarbamoyl-1-hydroxy-2,7-diaminomitosenes (11 and 12), and trans- and cis-10-decarbamoyl-1,10-dimethoxymitosenes (16 and 17) in acidic-to-neutral aqueous and methanolic solutions, respectively. (2) Between "pH" 6.0 and 7.0, the difunctionalized mitosene adducts accounted for nearly half of the product profile even though noticeable amounts of unreacted 1 remained. (3) Significant amounts of C-1 electrophilic products were not observed under acidic conditions. The product profiles observed with the second Cr(ClO4)2-mediated reductive procedure were markedly different. Activation of 1 was accomplished by the prior addition of Cr(ClO4)2 to excess cis-10-decarbamoyl-1,10-dimethoxy mitosene (17) to generate the putative mitosene monochromate 20 and mitosene dichromate 21 species in situ, followed by the addition of 1 (1 equiv per Cr(ClO4)2). The products obtained by using this protocol were similar to those observed with conventional reductants in which C-1 electrophilic adducts predominated in acid, C-1 nucleophilic products were the major products under neutral and basic conditions, and little modification of the C-10 site was detected throughout the "pH" range examined. The product profiles coupled with select auxiliary experiments have provided information concerning the mechanism of both reductive procedures. The major products furnished by using the direct Cr(ClO4)2-mediated procedure under acidic and neutral conditions have been attributed to the two one-electron reductions of 1 to give the bis-CrIII-bound species 22. Complexation of the C-5 and C-8 phenolic-type oxygens in reduced 1 is believed to facilitate the loss of methanol at C-9 and C-9a in 1 and the nucleophilic substitution processes at C-1 and C-10 as well as inhibit the electrophilic transformations at both DNA bonding sites. Explanations and supporting data have also been provided to account for the other products detected in these reactions. Correspondingly, the second procedure is conjectured to occur by an outer-sphere electron-transfer process from 20 and/or 21 to 1 to give the uncomplexed hydroquinone (or semiquinone) mitomycin C species 2. Subsequent loss of methanol at C-9 and C-9a yields the activated mitosene capable of furnishing the C-1 functionalized adducts 7 and 9 + 10. The distinctive product profiles observed with the direct addition of Cr(ClO4)2 to 1 and the remarkable high yields of C-1, C-10 dinucleophilic substitution adducts suggest that similar pathways may be operative in the in vivo process to provide the DNA-mitomycin C cross-link adducts. These notions are discussed in light of the DNA sequence selectivity recently observed for the drug monoalkylation bonding process.
Electrochemical Reductive Activation of Mitomycin C
Andrews, Paul A.,Pan, Su-Shu,Bachur, Nicholas R.
, p. 4158 - 4166 (2007/10/02)
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-pyrroloindole-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-pyrroloindole-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.
