Mitomycin A and

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. ... 

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... 

Mitomycin A and B differ in substituents at positions 7,9a, and the aziridine nitrogen. 

Beijnen JH, van der Houwen OAGJ, Rosing H and Underberg WJM, A systematic study on die chemical stability of mitomycin A and mitomycin B, Chem. Pharm. Bull., 34,2900-2913 (1986)."... 

Since the first total synthesis of mitomycins A and C was described in 1977 (77TL4295), many syntheses have been devised and many analogs prepared (79MI3 86JOC4307 87JMC168). A 17-step synthesis of 7-methoxymitosene (31, R = = H, X = MeO) from 6-methylindole produced 3% overall yield... 

The production, isolation from Streptomyces caespitosus, and properties of the first two component members of the mitomycin antibiotic complex, namely mitomycins A and mitomycin B, were described in 1956 (Figure 3.19) [32], The third component, mitomycin C, was described in 1958 [33]. The fourth mitomycin, named porfiromycin, was reported in 1960 [34], One year later, the fifth component of the... 

It was found by Hata et al. of the Kitasato Institute that a culture broth of Streptomyces caepitosis exhibited strong antimicrobial activity against Grampositive bacteria, and the active components were isolated and named as mitomycins A and B [1],... 

B, and C and porfiromycin also were produced by a Micromonospora species KY 11084 [65]. Mitomycins A and C showed antimicrobial activity against Bacillus subtilis and Klebsiella pneumoniae [66]. 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

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]. 

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-... 

The importance of superoxide-mediated damage to cancer cells was also demonstrated in the experiments with overexpressed mitochondrial MnSOD. Hirose et al. [186] showed that the overexpression of mitochondrial MnSOD enhanced the survival of human melanoma cells exposed to cytokines IL-1 and TNF-a, anticancer antibiotics doxorubicin and mitomycin C, and y-irradiation. Similarly, Motoori et al. [187] found that overexpression of MnSOD reduced the levels of reactive oxygen species in mitochondria, the intracellular production of 4-hydroxy-2-nonenal, and prevented radiation-induced cell death in human hepatocellular... 

Krishnaja, A.P. and M.S. Rege. 1982. Induction of chromosomal aberrations in fish Boleophthalmus dussumieri after exposure in vivo to mitomycin C and heavy metals mercury, selenium and chromium. Mutat. Res. 102 71-82. 

Lim and Sulikowski (84) explored the intramolecular C-H insertion in 119 alpha to the nitrogen atom as a rapid entry to the mitomycin skeleton and the antitumor agent FR-900482. Rhodium(II) based catalysts provide nearly racemic products. Bis(oxazoline) (55b) affords highest selectivities in this system and chloroform was found to be the optimal solvent, Eq. 71. The authors note that the reaction is somewhat capricious. 

G. M. Dubowchik, K. Mosure, J. O. Knype, R. A. Firestone, Cathepsin B-Sensitive Dipeptide Prodrugs. 2. Models of Anticancer Drugs Pachtaxel, Mitomycin C and Doxorubicin , Bioorg. Med. Chem. Lett. 1998, 8, 3347-3352. 

Keane TJ, Cummings B J, O Sullivan B, et al. A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma. Int J Radiat Oncol Biol Phys 1993 25 613-618. 

Patients receiving concurrent chemoradiotherapy had a significant improvement in median survival (14 vs 9 mo) and 5-yr survival (26% vs 0%,p< 0.0001) (43). Even with further follow-up, the 8-yr survival remained 22% (44). The incidence of local failure (defined as persistent disease, as well as the first site of failure) was significantly decreased in the combined modality arm (45% vs 68%, p = 0.0123). Although randomization was discontinued early due to the positive results, an additional 69 patients treated with the same chemoradiation regimen had similar results (3-yr survival = 30%) (43-45). A second randomized study of chemoradiotherapy to radiation alone found a significant improvement in median survival (14.8 vs 9.2 mo, p = 0.04), but no difference in 5-yr survival (9% vs 7%). The chemotherapy consisted of 5-FU, mitomycin-C, and radiation. This was not, however, purely a comparison of concurrent chemoradiation to radiation alone, as almost 50% of patients in each arm went on to surgery. The operative mortality was 17% (46). 

Trials of cisplatin-based chemoradiation have not yet demonstrated any dramatic increase in the incidence of major late complications with the addition of concurrent cisplatin. However, most of these trials did not have sufficiently mature follow-up at the time of publication to permit full evaluation of the comparative risks. Thomas et al. (35) reported a significantly higher rate of serious late bowel complications in patients who received mitomycin with or without fluorouracil than in patients who received fluorouracil alone (p = 0.004). However, Roberts etal. (27) have not yet reported an increased rate of late complications with chemotherapy in their Venezuelan study of radiation alone vs radiation plus mitomycin C and fluorouracil. Long-term follow-up of the randomized trials will be needed to improve our understanding of the influence of concurrent chemotherapy on late complications. 

Christie DR, Bull C A, Gebski V, etal. Concurrent 5-fluorouracil, mitomycin C and irradiation in locally advanced cervix cancer. Radiother Oncol 1995 37 181-189. 

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