92695-32-4

Upstream product

• 50-07-7 mitomycin C 
• 127-09-3 sodium acetate 
• 103422-25-9 7-aminoaziridinomitosene 

Relevant academic research and scientific papers

Reductive activation of mitomycins A and C by vitamin C

The anticancer drug mitomycin C produces cytotoxic effects after being converted to a highly reactive bis-electrophile by a reductive activation, a reaction that a number of 1-electron or 2-electron oxidoreductase enzymes can perform in cells. Several reports in the literature indicate that ascorbic acid can modulate the cytotoxic effects of mitomycin C, either potentiating or inhibiting its effects. As ascorbic acid is a reducing agent that is known to be able to reduce quinones, it could be possible that the observed modulatory effects are a consequence of a direct redox reduction between mitomycin C and ascorbate. To determine if this is the case, the reaction between mitomycin C and ascorbate was studied using UV/Vis spectroscopy and LC/MS. We also studied the reaction of ascorbate with mitomycin A, a highly toxic member of the mitomycin family with a higher redox potential than mitomycin C. We found that ascorbate is capable to reduce mitomycin A efficiently, but it reduces mitomycin C rather inefficiently. The mechanisms of activation have been elucidated based on the kinetics of the reduction and on the analysis of the mitosene derivatives formed after the reaction. We found that the activation occurs by the interplay of three different mechanisms that contribute differently, depending on the pH of the reaction. As the reduction of mitomycin C by ascorbate is rather inefficiently at physiologically relevant pH values we conclude that the modulatory effect of ascorbate on the cytotoxicity of mitomycin C is not the result of a direct redox reaction and therefore this modulation must be the consequence of other biochemical mechanisms.

Studies on the use of Na2S2O4 for the reductive activation of mitomycin C

Mitomycin C (1a) is considered to be the prototypical bioreductive alkylating agent. Among the numerous reductive procedures employed for the in vitro activation of mitomycin C, incremental addition of Na2S2O4 has emerged as the method of choice for generating high yields of mitomycin C-DNA adducts. The major products and distinguishing features of the incremental addition Na2S2O4-mitomycin C reductive processes in water (pH 7.4) in the absence of DNA are reported. Key observations included (1) rapid and efficient consumption of mitomycin C, (2) production of high amounts of 7-aminomitosane-9a-sulfonate (1b) in the early stages of the reaction, and (3) generation of significant amounts of C(1) and C(10) sulfonato adducts. The complexity of this transformation has been attributed in part to HSO3-, a byproduct of the Na2S2O4 reduction process. Use of buffered methanol solutions ("pH" 7.4) in place of water simplified the product profile. The poor solubility of Na2S2O4 and NaHSO3 in methanol produced only trace amounts of mitosene sulfonato adducts. There were significant differences between product profiles for the incremental addition Na2S2O4 procedure versus a protocol in which the equivalent amount of Na2S2O4 was added in a single shot. First, higher amounts of C(1) electrophilic versus C(1) nucleophilic products were observed using the single shot technique. Second, C(1) sulfonato adducts composed a larger amount of the C(1) nucleophilic product pool when the Na2S2O4 was added using the single shot protocol than with the incremental addition method. Third, higher amounts of 1a were converted to C(1), C(10) fully functionalized mitosene adducts using the incremental procedure. Select auxiliary experiments provided additional information concerning the Na2S2O4-mediated mitomycin C reductive process. Examination of the reactivity of key C(1), C(9a), and C(10) mitomycin sulfonato products demonstrated that 7-aminomitosane-9a-sulfonate (1b) was efficiently converted to C(1)- and C(10)-functionalized mitosenes under reductive conditions, whereas mitosene C(1) and C(10) sulfonates did not undergo displacement reactions and hence did not function as viable alkylating agents. On the basis of these cumulative studies, we suggest the likely mechanism for the Na2S2O4-mediated mitomycin C reductive process and the beneficial properties accrued by the use of the incremental addition technique. These notions are discussed in light of the pathway that may be operative in in vitro mitomycin C-DNA bonding transformations.

Studies on the reactivity of reductively activated mitomycin C

Mitomycin C (1a), a clinically significant antineoplastic antiobiotic, is considered to be the prototype of bioreductive alkylating agents. It has been reported that, in the absence of DNA, reductive activation of 1a furnished both solvolytic C(1) electro

Sodium dithionite-mediated mitomycin C reductive activation processes

Sodium dithionite is the reagent of choice for the reductiue activation of mitomycin C in the presence of DNA. No comprehensive study of this transformation in the absence of DNA has appeared. The major products of this reaction have been determined and the key parameters governing this transformation identified.

Studies on the Use of Cr(ClO4)2 for the Reductive Activation of Mitomycin C 1

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

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.