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The bleomycin molecule is finely tuned for its function, and its various structural portions act synergistically to affect efficient DNA cleavage, with the roles summarized in Fig. 4.28.74 The bleomycin-iron complex is formed at the metal-binding domain, comprising the p-aminoalanine-pyrimidine-p-hydroxyhistidine moiety. This portion of the molecule contains five nitrogen atoms at a distance suitable to form a stable chelate with Fe (II), leaving a sixth coordination valence available for a molecule of oxygen. Regarding the mode of interaction of the bleomycins with DNA, it involves two types of interactions, one of them being electrostatic binding of the cationic or protonated amino side chain with DNA phosphate groups, as proved by the observation that nonbasic side chains, although more easily transported into the cells, are much less active. The role of the bisthiazole system in DNA interaction has also been thoroughly studied, and two binding modes seem possible, namely intercalation and binding into the minor groove. Since DNA strand scission starts by abstraction of the deoxyribose 4'-hydrogen, which lies in the minor groove, it seems likely that bleomycin binds there, but intercalation has also been proved by the lengthening of linear DNA or the uncoiling of circular DNA.75 Bleomycin shows selectivity toward 5'-GC-3' and 5'-GT-3' sequences because of hydrogen bonding recognition, either of the bithia-zole unit or of the aminopyrimidine function.76,7 Finally, the sugar moiety may be responsible for the uptake of the drug into cells but it does not seem to be involved in DNA cleavage, although it has been prop78osed that it has a role in the capability of the bleomycins to accommodate oxygen. 8 The linker region is also essential for

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