98462-75-0Relevant articles and documents
Synthesis of Mitomycin C and Decarbamoylmitomycin C N2 deoxyguanosine-adducts
Champeil, Elise,Cheng, Shu-Yuan,Huang, Bik Tzu,Conchero-Guisan, Marta,Martinez, Thibaut,Paz, Manuel M.,Sapse, Anne-Marie
, p. 90 - 99 (2016/03/01)
Mitomycin C (MC) and Decarbamoylmitomycin C (DMC) - a derivative of MC lacking the carbamate on C10 - are DNA alkylating agents. Their cytotoxicity is attributed to their ability to generate DNA monoadducts as well as intrastrand and interstrand cross-lin
A mitomycin-N6-deoxyadenosine adduct isolated from DNA.
Palom, Jolanda,Lipman, Roselyn,Musser, Steven M.,Tomasz, Maria
, p. 203 - 210 (2007/10/03)
A minor N6-deoxyadenosine adduct of mitomycin C (MC) was isolated from synthetic oligonucleotides and calf thymus DNA, representing the first adduct of MC and a DNA base other than guanine. The structure of the adduct (8) was elucidated using submilligram quantities of total available material. UV difference spectroscopy, circular dichroism, and electrospray mass spectroscopy as well as chemical transformations were utilized in deriving the structure of 8. A series of synthetic oligonucleotides was designed to probe the specificities of the alkylation of adenine by MC. The nature and frequency of the oligonucleotide-MC adducts formed under conditions of reductive activation of MC were determined by their enzymatic digestion to the nucleoside level followed by quantitative analysis of the products by HPLC. The analyses indicated the following: (i) (A)n sequence is favored(AT)n for adduct formation; (ii) the alkylation favors the duplex structure; (iii) at adenine sites only monofunctional alkylation occurs; (iv) the adenine-to-alkylation frequency in the model oligonucleotides was 0.3-0.6 relative to guanine alkylation at the 5'-ApG sequence but only 0.02-0.1 relative to guanine alkylation at 5'-CpG. The 5'-phosphodiester linkage of the MC-adenine adduct is resistant to snake venom diesterase. The overall ratio of adenine to guanine alkylation in calf thymus DNA was 0.03, indicating that 8 is a minor MC-DNA adduct relative to MC-DNA adducts at guanine residues in the present experimental residues in the present experimental system. However, the HPLC elution time of 8 coincides with that of a major, unknown MC adduct detected previously in mouse mammary tumor cells treated with radiolabeled MC [Bizanek, R., Chowdary, D., Arai, H., Kasai, M., Hughes, C. S., Sartorelli, A. C., Rockwell, S., and Tomasz, M. (1993) Cancer Res. 53, 5127-5134]. Thus, 8 may be identical or closely related to this major adduct formed in vivo. This possibility can now be tested by further comparison.
Studies on the use of Na2S2O4 for the reductive activation of mitomycin C
Schiltz, Pascal,Kohn, Harold
, p. 10497 - 10509 (2007/10/02)
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.
