The Mitomycins and Porfiromycins

Abstract

The mitomycins and porfiromycins form a group of closely related bactericidal and cytotoxic antibiotics produced by several Streptomyces species. They all can be derived from a common structure, the trivial name of which is mitosane (I, Fig. 1), as first recognized and named by WEBB et al. (1962). This rather unusual compound contains several reactive groups, including 1. the highly strained aziridine ring (1-1a-2), 2. amino-or methoxybenzoquinone (5a-5-6-7-8-8a), 3. the pyrrolizidine configuration (l-2-3-4-5a-8a-9-9a), and 4. a methylurethane side chain (10–l0a). The various natural mitomycins and porfiromycins vary in the nature of the ring substitutions in positions 1a (hydrogen or methyl), 7 (amino, or methoxy) and 9a (methoxy of hydroxyl). It is not clear whether the nature of the substituents in positions 1a and 7 determines only quantitatively or also qualitatively the biological activity (Tables 1 and 2); substituent 9a should be a good leaving group, because of the aromatization afforded by loss of the 9a substituents, which promotes their elimination, as will become evident in the discussion on the mechanism of mitomycin action. The structures of the mitomycins and porfiromycins (Webb et al., 1962; Tulinsky, 1962; Herr et al., 1961; Wakaki, 1961; Stevens et al., 1965) are shown in Fig. 2. The structures of two other mitomycin-associated antibiotics A₁ and A₂ (mitiromycin) are unknown (Lefemine et al., 1962). Three more compounds, which are synthetic products but can be regarded as partially rearranged or degraded mitomycins, and which were shown to possess bactericidal activity, include 7-hydroxyporfiromycin (Fig. 2; Garrett and Schroeder, 1964), 7-methoxymitosene (Fig. 3 A; Allen et al., 1964a, 1965) and 7-methoxy-1, 2-(N-methylaziridino)mitosene (Fig. 3 B, Patrick et al., 1964). 7-Methoxymitosene, which is only very remotely related to mitomycins, can be regarded as a monofunctional agent, whereas the other two compounds are bifunctional alkylating agents. A group of antibacterial indoloquinones related in structure and action to 7-methoxymitosene was described by Allen et al. (1964b), Remers and Weiss (1966) and Roth etal. (1966). Other more recent papers discussing the chemistry of the mitomycins include those of Allen et al. (1965, 1966), Allen and Weiss (1965), Remers et al. (1963, 1964, 1965), Remers and Weiss (1965), and Stevens et al. (1965).