Mitomycin C, structure

Microwaves, electromagnetic spectrum and. 419 Mincralocorticoid, 1083 Minor groove (DNA), 1104-1105 Mitomycin C, structure of, 970 Mixed aldol reaction, 885-886 requirements for. 885-886 Mixed Claisen condensation reaction, 890-891... 

Leptosins D-F (258a-c, Scheme 39) [94JCS(P1)1859] were isolated by Takahashi and co-workers from the culture of a strain of Leptosphaeria sp. as cytotoxic substances against the P388 lymphocytic leukemia cell line comparable to that of mitomycin C. Utilizing the nucleophilic substitution reaction of 1-hydroxytryptamines, a simple methodology for the synthesis of core structures of leptosins has been developed (2000H1255). 

The different possible adducts formed between mitomycin C and DNA have been isolated by degradation of DNA after in vitro alkylation/crosslinking reactions and structurally characterized. Monoadduct 21 (Scheme 11.3), derived from alkylation at C-l only [53], and monoadducts 22 [54] and 23 [55, 56] (derived from C-10 alkylation by 16 at N-7 or N-2 of guanine, respectively) have been isolated, together with bisadducts 24 [57] and 25 [58], derived from interstrand and intrastrand crosslinks, respectively, and adduct 26 [59], formed by addition of a molecule of water to C-10 instead of the second guanine. All of these adducts have also been isolated from DNA after in vivo crosslinking [60, 61]. 

The rationale for the cyclopent[Z>]indole design discussed above was that the quinone methide would build up in solution and intercalate/alkylate DNA. Enriched 13C-NMR studies indicate that the quinone methide builds up in solution and persists for hours, even under aerobic conditions (Fig. 7.21). In contrast, the quinone methide species formed by known antitumor agents (mitomycin C) are short lived and highly reactive. The spectrum shown in Fig. 7.21 also shows the N to O acyl transfer product that we isolated and identified. However, we could not determine if the quinone methide structure actually has the acetyl group on the N or O centers. 

The feasibility of identifying these edges of water base pairs has been supported by our studies of mitomycin C interacting with the model system for AT base pairs 29). Interactions of either component with mitomycin C are not observed but a complex is formed when all three components are present. Chemical shift changes observed in the NMR spectra support the structure 47 for the termolecular complex. The broader implication is that mitomycin C will likewise recognize the minor groove side of a G-C pair (it is known to alkylate the guanidine on this side)31 ... 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Tomasz, M., Chowdary, D., Lipman, R., Shimotakahara, S., Veiro, D., Walker, V., Verdine, G. L. Reaction of DNA with Chemically or Enzymatically Activated Mitomycin C Isolation and Structure of the Major Covalent Adduct. Proc. Natl. Acad. Sci. USA. 1986, 83, 6702-6706. 

Pan, S., Andrews, P.A., Glover, C.J., and Bachur, N.R., 1984, Reductive activation of mitomycin C and mitomycin C metabolites catalysed by NADPH-cytochorome P-450 reductase and xantine oxidase. J. Biol. Chem. 259 959-962 Pollakis, G., Goormaghtigh, E., and Ruysschaert, J.-M., 1983, Role of quinone structure in the mitochondrial damage induced by antitumor anthracyclines. FEBS Lett. 155 267-272 Rappaport, S.M., McDonald, T.A., and Yeowell-O Connell, K., 1996, The use ofprotein adducts to investigate the disposition of reactive metabolites of benzene. Environ. Health Perspect. 104Suppl6 1235-1237... 

Compounds whose structures include a quinone moiety have been intensively investigated as potential antitumor agents. At least two quinones, mitomycin C and diaziquone, that have found their way to the clinic. These compounds in addition include a reactive aziridine ring. A recent entry that incorporates both those features, apaziquone (135), also known as E09, may be viewed as an oxidized indole. In the key reaction of a succinct synthesis to this agent, quinone 129 is allowed to react with... 

Martin TW, Dauter Z, Devedjiev Y, Sheffield P, Jelen F, He M, Sherman DH, Otlewski J, Derewenda ZS, Derewenda U. Molecular basis of mitomycin C resistance in streptomyces structure and function of the MRD protein. Structure 2002 10(7) 933—942. Sheldon PJ, Johnson DA, August PR, Liu HW, Sherman DH. Characterization of a mitomycin-binding drug resistance mechanism from the producing organism, Streptomyces lavendulae. J. Bacteriol. 1997 179(5) 1796-1804. 

Microbial sources have been a very rich source for cancer chemotherapeutic agents. Of particular note is the Strep-tomyces spp., which has been responsible for the production of many approved anticancer agents that are in clinical practice. These agents are represented by highly diverse structural classes exemplified by the anthracycline family (e.g., doxom-bicin, 73) (72-74), actinomycin family (e.g., dactinomycin, 74), glycopeptides family (e.g., bleomycins A2 and B2, 75 and 76) (75), and mitomycin family (e.g., mitomycin C, 77) (72, 76). All these compounds specifically interact with DNA for then-mode of action. 

Biedler and coworkers [123] reported that Chinese hamster cells selected for resistance to actinomycin D also showed cross-resistance to mithramycin, vinblastine, vincristine, puromycin, dauromycin, democolcine, and mitomycin C. Thus, upon selection with a single cytotoxic drug, mammalian cells became simultaneously cross-resistant to a range of drugs with different chemical structures and molecular... 

Drug substances such as sulpyrine,98" furosemide,100101 thiamine hydrochloride,102 diethylpropion,103 mitomycin C,104 105 zileuton,106 and cifenline107 have reactive nitrogens in their molecular structure and undergo hydrolysis, as shown in Scheme 21. The derivatives of 3,4-dihydro-l,3-benzoxazine and 3,4-dihydro-l,3-pyridooxazine undergo ring opening due to hydrolysis accompanied by elimination of formaldehyde (Scheme 22).108... 

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