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oconh2

R = H Mitomycin C R = Me Porfiromycin

Mitomycin C and porfiromycin can be considered as the prototype of reduc-tively activated alkylating agents. The most common structural motif in these compounds is the quinone, which has reduction potentials similar to the substrates of reductases. These compounds are particularly useful for the treatment of hyp-oxic tumors because in these environments the bioreduction to hydroquinones is not reversed by oxygen, and can also act as radiosensitizers.18 Hypoxia-based strategies for tumor-specific prodrug activation are studied in more detail in Section 2.2 of Chapter 11.

The main mechanism of action of mitomycin is a characteristic example of an in situ bioreductive activation19 leading to cytotoxic species (Fig. 6.6). It involves two consecutive one-electron reduction steps to the corresponding semiquinone 6.1 and then to hydroquinone 6.2. Both forms can initiate the cascade of reactions leading to DNA alkylation, but available evidence points at hydroquinone as the active species.20 Furthermore, human carcinoma cell lines with high levels of DT-diaphorase, an obligate two-electron reducing enzyme that cannot generate

FIGURE 6.6 Bioreductive activation of mitomycin C.

intermediate semiquinones, show greater susceptibility to mitomycin, which is inhibited by treatment with diaphorase inhibitors.21 Spontaneous elimination of methanol from hydroquinone 6.2 gives the iminium derivative 6.3; this reaction takes place only in aqueous solution, which suggests that protonation of the leaving group by water is essential.22 A similar elimination reaction is not possible in mitomycin because the N-4 nitrogen lone pair is conjugated with one of the quinone carbonyls, leading to a vinylogous amide structure. Indole derivative 6.4, formed by deprotonation of 6.3, contains two good leaving groups, namely the aziridine ring and the carbamate. Protonation of the aziridine nitrogen of 6.4 and subsequent elimination with concomitant opening of the aziridine ring affords quinone methide 6.5. This highly reactive intermediate contains an electrophilic position that reacts with nucleophilic groups on DNA through a Michael-type reaction to give the unstable intermediate 6.6. This reaction proceeds with absolute specificity towards certain sequences at the minor groove (see below), and involves the guanine N-2 amino group or N-7 position as nucleophiles. Elimination of the carbamate group generates an electrophilic iminium species, which undergoes a second alkylation by attack from a guanine 2-amino group, and leads to DNA cross-linking products 6.7.23

Both inter- and intrastrand cross-linking by mitomycin has been observed, although the former is predominant. Inter- and intrastrand cross-linking are specific, respectively, to 5'-CG24 and 5'-GG25 sequences in the minor groove.26 This selectivity arises from the first alkylation event and has been explained in terms of hydrogen bonding between the guanine N-2 amino group27,28 and one of the carbamate oxygens, as shown in the models in Fig. 6.7, which are based on high-resolution NMR and molecular modelling studies.28

Intermediates similar to 6.2 are generated from the aziridine alkaloids FR-900482 and FR-69979, isolated from a culture broth of S. sandaenis. These compounds give interstrand cross-linking reactions with the same selectivity as mitomycin.29 The cascade of reactions is initiated by bioreductive activation involving cleavage of the N-O bond to give the eight-membered ketone 6.8, which is transformed into 6.9 by intramolecular nucleophilic attack of the amino group thus generated onto the ketone carbonyl. Evolution of this intermediate as described for 6.2 gives quinone methide intermediate 6.11, which is very similar to mitomycin intermediate 6.5, and leads to DNA cross-linking products by a similar mechanism involving amino groups at the guanine N-2 position (Fig. 6.8).30,31 Covalent cross-linking between the DNA minor groove and DNA-binding proteins has also been described.32

FR-900482 and FR-69979 are more efficient cross-linking agents than mitomycin. This can be explained in terms of the dual nucleophilic-electrophilic character of the quinone methide 6.5 generated from the latter, which facilitates its protonation at C-1, 3 a reaction that competes with nucleophilic attack from DNA (Fig. 6.9). In spite of their apparent similarity, intermediates 6.11 generated from the FR compounds lack nucleophilic character due to the absence of a C5-OH group conjugated with the C-1 position.

The unique mechanism of action and clinical success of mitomycin, coupled to its high toxicity, has prompted the preparation of a large number of synthetic

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