Mitomycin A

Mitochondrial monoamine oxidase, 1, 253 Mitomycin synthesis, 7, 658, 659 Mitomycin-A, 7, 93 Mitomycin-B, 7, 93 Mitomycin-C, 7, 93 as antitumor drug, 4, 374 Mixed function oxidases, 1, 224 Mobam... 

A 3-acetoxypropyl group was used to protect an aziridine — NH group during the synthesis of mitomycins A and C acetyl, benzoyl, ethoxycarbonyl, and methoxymethyl groups were unsatisfactory. ... 

Sherman et al. have analyzed the function of the MitM methyltransferase in more detail [113]. They knocked out the MitM gene and found that mitomytin C production was abolished, and were able to isolate a small quantity of 9a-demethyl mitomycin A (62) from this mutant (Figure 11.9). MitM was expected to act as an O-methyltransferase, but surprisingly recombinant MitM converted 62 into 9-epi-mitomydn B (63), hence acting as an aziridine N-methyltransferase. Mitomy-... 

Palom, Y. Lipman, R. Musser, S. M. Tomasz, M. A mitomycin-A-6-deoxyadenosine adduct isolated from DNA. Chem. Res. Toxicol. 1998, 11, 203-210. 

Fukuyama and Yang (49) developed a highly efficient synthesis of the tetracyclic intermediate 241, used in a total synthesis of mitomycin A (Scheme 9.49). The required azide 240 was produced from 239 in several steps. Upon heating in refluxing toluene, the azide 240 underwent smooth intramolecular cycloaddition with the unsaturated lactone followed by extrusion of nitrogen to give aziridine 241 in 85% yield. 

An intriguing tripartite interconversion of mitomycin A, albomitomycin A, and isomitomycin A is the result of a Michael and a retro Michael reactions [137]. The transformation of mitomycin A to albomitomycin A formally involves a cis addition, that from iromitomycin A, a tram addition. 

Model Studies for Mitomycin A Synthesis Lead to a New Preparation of Pyrroloindoles... 

Mitomycin A, 1, is a natural product which shows potent antibiotic and antitumor activity, and has been the subject of extensive synthetic studies. French workers have described a simple procedure for one-pot preparation of the tricyclic skeleton of the mitomycins. Thus, simply mixing and stirring a solution of nitrosobenzene and (E,E)-hexa-2,4-dienal in absolute ethanol at... 

Antitumor agents mitomycin A (61 A) and mitomycin C (61C) contain a latent quinone functionality, which is exposed by reductive activation and elimination of a glycoside or an alcohol followed by opening of the aziridine ring. These quinone methides then react with nucleic acids to form bis-adducts.103 The reductive activation of mitomycins provides selectivity in targeting solid tumors, because this is favored in the oxygen-deprived environment of tumor cells, and inhibited by the oxygen-rich environment of healthy tissues.107... 

The reductive activation of mitomycins in the cell is thought to be an enzymatic process.108 Reduction of mitomycins A and C in vitro by H2/Pt02 or by Na2S204 gives 62, which then breaks down to the quinone methide 63A.109 This quinone methide reacts with DNA to give a complex mixture of alkylated DNA and cross-linked oligonucleotides. Mitomycin A is both more easily reduced and more toxic than mitomycin C, and there is some evidence that the toxicity of... 

In the case of synthetic studies on mitomycins (e.g. mitomycin A), both techniques were applied to synthesize model compounds. A retro aldol reaction, followed by a trivial transannular reaction, was performed in the same pot and under the same conditions (sodium hydride) [79] [80], Scheme VIII/25. Thus, compound VIII/132 gave the ring closed intermediate, VIII/133, which by a retro aldol reaction, yielded the eight-membered intermediate, VIII/134. A transannular reaction in VIII/134 gave the acid labile VIII/135, which led finally to the indole derivative, VIII/136. 

In an analogous manner the indole double bond in VIII/203 was opened oxidatively (02, rose Bengal, 200 W halogen lamp, CH3OH/CH2Cl2, 25, 5 h) and the desired eight-membered lactam VIII/204 was isolated in 82% yield [118]. Compound VIII/204 is an intermediate in a synthetic approach to the potent antitumor antibiotic mitomycin A (see Chapter VIII.2). 

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