Of mitomycins

Aziridines occur naturally in the form of mitomycins (Table 3), which have antibiotic activity (1,449). Mytomycin C is used clinically as one of the most effective agents in the chemotherapy of cancer (450). 

Analogous chemistry with 2,3-dibromo-l,4-naphthoquiaone [13243-65-7] (102) has been used ia the synthesis of mitomycin antibiotics for example, (103) [72866-63-8]h.2iS been obtained ia 91% yield (102). 

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. ... 

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). 

Figure 11.16 Chromatograms of plasma samples obtained by using SPE-SFC with super-aitical desorption of the SPE cartridge (a) blank plasma (20 p.1), UV detection at 215 nm (b) blank plasma (20 p.1), UV detection at 360 nm (c) plasma (1 ml) containing 20 ng mitomycin C (MMC), UV detection at 360 nm. Reprinted from Journal of Chromatography, 454, W. M. A. Niessen et al., Phase-system switching as an on-line sample pretreatment in the bioanalysis of mitomycin C using supercritical fluid cliromatography, pp. 243-251, copyright 1988, with permission from Elsevier Science.

W. M. A. Niessen, R J. M. Bergers, U. R. Tjaden and J. van der Greef, Phase-system switclring as an on-line sample preti eatment in the bioanalysis of mitomycin C using supercritical fluid clrromatogi aphy , 7. Chromatogr. 454 243-251 (1988). 

The commercial production of mitomycin involves the preparation of mitomycin-containing broths by culturing a mitomycin-producing organism, e.g. Streptomyces caespitosus, in suitable media as described at length In the literature. At the end of the fermentation cycle the whole broth is usually centrifuged, filtered or otherwise treated to separate the solids (mycelia) from the supernatant which contains substantially all of the antibiotic activity. 

Figure 11.3 Biosynthetic origin of the O-methyl and carbamoyl groups of mitomycin C.

Figure 11.4 Carbohydrate precursors to the carbon skeleton of mitomycin C.

A number of mitomycin analogues have been prepared by precursor-directed biosynthesis [104]. A range of amines were fed to S. caespitosus, and novel derivatives of mitomycin C (type I analogues) and mitomycin B (type II analogues) were identified and in some cases (42-46 and 52-56 Scheme 11.4) isolated and characterized. Antibiotic and antitumor activities were comparable to those of mitomycin C, with the type I analogues more active than the type II analogues. 

The continuing interest in bioreductive alkylation is largely due to the clinical success of mitomycin C and the low reduction potentials observed in many tumors.9 The low reduction potentials favor the quinone to hydroquinone conversion necessary for bioreductive alkylation. Hypoxia due to low blood flow3 and/or the unusually high expression of the quinone two-electron reducing enzyme DT-diaphorase in some histological cancer types10-14 contribute to the tumor s tendency to reduce quinones. 

Dithionite-mediated reductive activation of mitomycin C has been employed in the study of its DNA alkylation chemistry.6,63 However, dithionite activated mitomycin C possesses different DNA alkylation properties than that activated by catalytic hydrogenation and enzymatic reduction. We postulated that a new alkylating species is produced by dithionite reductive activation resulting in different reactivity than the iminium methide species. To investigate dithionite-mediated reductive activation further, we treated 13 C-labeled analogues of WV-15 with dithionite and carried out spectral and product studies. 

Belcourt, M.F. Hodnick, W. F. Rockwell, S. Sartorelli, A. C. Bioactivation of mitomycin antibiotics by aerobic and hypoxic Chinese hamster ovary cells overexpressing DT-diaphorase. Biochem. Pharm. 1996, 51, 1669-1678. 

Tomasz, M. Mercado, C. M. Olson, J. Chatteijie, N. The mode of interaction of mitomycin C with deoxyribonucleic acid and other polynucleotides in vitro. Biochemistry 1974, 13, 4878-4887. 

Mitomycin C is an alkylating agent that forms cross-links with DNA to inhibit DNA and RNA synthesis. The pharmacokinetics of mitomycin C are best described by a two-compartment model, with an a half-life of 8 minutes and a terminal half-life of 48 minutes.31 Liver metabolism is the primary route of elimination. Mitomycin C has shown clinical activity in the treatment of anal, bladder, cervix, gallbladder, esophageal, and stomach cancer. Side effects consist of myelosuppression and mucositis, and it is a vesicant. 

T Yoshioka, M Hashida, S Muranishi, H Sezaki. Specific delivery of mitomycin C to the liver, spleen, and lung Nano-and microspherical carriers of gelatin. Int J Pharm 8 131-141, 1981. 

Table 13 Mitomycin Concentration (mg/g) in Tumors and Organs After Intraperitoneal Administration of Mitomycin-Activated Carbon and Mitomycin in Saline Solutions (dose 2 mg/kg)... 

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 ... 

Several approaches have been developed for the total synthesis of mitomycins, but only few of them were enantioselective. In Scheme 71 are summarized the main strategies described for the synthesis of more or less functionalized mitomycinoids. 

FIGURE 5.12 Bioactivation of mitomycin C, the first step of which involves reduction of the quinone. 

Suresh Kumar G, Lipman R, Cummings J, et al. Mitomycin C-DNA adducts generated by DT-diaphorase. Revised mechanism of the enzymatic reductive activation of mitomycin C. Biochemistry 1997 36(46) 14128—14136. 

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