Depurinized DNA

FIGURE 5.3 DNA fragmentation triggered by guanine alkylation.

leaving group (phosphate oxygen) at the p position with respect to the carbonyl group. This arrangement leads to an easy elimination process whereby DNA is fragmented to 5.5 and 5.6 (Fig. 5.3).

Another position of the purine ring with increased electrophilicity is C-8, which is adjacent to the positive charge induced on alkylation. Water addition to C-8 leads to intermediate 5.7, which then evolves to 5.8. This compound has an imine structure that allows hydrolysis and gives 5.4 with subsequent DNA strand scission (Fig. 5.4).

Because nitrogen mustards are bifunctional alkylating agents, one of their cytotoxicity mechanisms is related to the ability of DNA-monoalkylated species 5.9 to give covalent DNA interstrand and intrastrand cross-links (5.10) or DNAprotein complexes (5.11) from the monoalkylated species 5.9, leading to disruption of replication or transcription (Figs. 5.1 and 5.5).

2.3. Structure-activity relationships in nitrogen mustards

Although mechlorethamine was an improvement over sulfur mustard, it was still highly vesicant and chemically labile because of its very rapid reaction with biological material and water, respectively. Replacement of its methyl group by an aromatic ring lowers its reactivity because the electron-withdrawing effect of this type of substituents hampers anchimeric assistance to alkylation by the nitrogen atom. The increased stability gives enough time for absorption and

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