Mitomycins structure

In this review, the trivial names mitosane and mitosene [14] (Fig. 1) will be used to describe various mitomycin structures. For example, mitomycin C is 7-amino-9a-methoxymitosane. It should be noted that the numbering of a mitosane differs from the systematic numbering used in Chemical Abstracts for azirino[2, 3 3,4]pyrrolo[l,2-a]indoles, wherein the aziridine nitrogen is the starting point. 

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). 

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... 

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 ... 

Iyer VN, Szybalski W (1963) A molecular mechanism of mitomycin action Linking of complementary DNA strands. Proc Natl Acad Sci U S A 50 355-362 Jamieson ER, Lippard SJ (1999) Structure, recognition, and processing of cisplatin-DNA adducts. Chem... 

The mitomycins (331) have attracted much attention as a result of their interesting structure and especially because of their potent anti-cancer properties [102]. One approach to these materials is illustrated in Scheme 22 [103]. A key intermediate in the implementation of this plan is azocinone 333, a substance... 

So far, not much literature on the biological activity of iminophosphor-anes has appeared. Compounds possessing triorganylphosphoranylidenea-mino structural elements such as mitomycin (41) have proved to be interesting anti-tumor reagents the cancerostatic activity seems to be localized in the aziridine units of 40 (Scheme 19) [87PS(30)845]. 

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... 

Alder reaction [524, 525]. Danishefsky et al. have used nitroso dienophiles for the synthesis of mitomycin K and antibiotics of the FR 900482 family, the latter ones are structurally unique aziridino-l,2-oxazine derivatives [526-529]. An approach directed to the cephalotaxus alkaloids has been worked out by Fuchs et al. [530], and several indolizidine alkaloids have been prepared by Keck s [531] and Kibayashi s groups [532,533]. Kibayashi et al. also synthesised Nuphar piperidine alkaloids in enantiomerically pure form by means of an asymmetric nitroso Diels-Alder reaction [534]. 

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... 

The most commonly used of these three bond classes is the formation of bond b . Formation of bond b typically occurs through an intramolecular alkylation of a nitrogen atom. A second highly prevalent method for the formation of the type I structure is the formation of bonds b and c from addition of a nitrogen across a carbon-carbon double bond. A final rarely used route is the formation of bonds c and e through the intramolecular addition of a carbene across and carbon-nitrogen double bond. Methods in which bond a is formed are rare in terms of simple fused-ring aziridines but several examples can be found in Section 1.02.7 in the discussion of the mitomycin family of alkaloids (Scheme 1). 

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