**9.1 Mitomycin-C**

*Biophysical Chemistry - Advance Applications*

Cisplatin-DNA sequence selectivity has been given great attention from the research community. Several studies show that cisplatin first binds monofunctionally to guanine N7 and is particularly reactive towards Gn-runs (n ≥ 2) (**Figure 7**) [18, 20, 21]. The high nucleophilicity of Gn-runs attracts the positively charged cisplatin monoaqua specie. The lifetime of the monoadduct is relatively long and it has therefore been suggested that the initial monoadduct is crucial for the type of cross-linked adduct formed and thus for the cytotoxic properties of the Pt complex. The main factors influencing the mono-functional binding affinity in DNA are thought to be [18] the type of bound nucleotide and of the adjacent residues, the steric effects of the Pt complex, the hydro-

The formation of a cisplatin adduct with the GpG bases requires a significant tilting of the bases leading to a perturbation of the regular B-DNA conformation. The structural perturbation has been shown to be specifically recognized by a number of cellular proteins, including proteins with high-mobility group (HMG) binding domains and the TATA box binding protein [22]. It is believed that (some of) these recognition proteins mediate the cellular response which finally induces cell death by apoptosis or necrosis. In some cases, relatively subtle changes in the adduct structure can affect the recognition and the biological effects in a major way. This is exemplified by the cisplatin analogue oxaliplatin which forms similar G\*G\*-Pt adducts as cisplatin [18]. However, the oxaliplatin-G\*G adducts differ in repair efficiency, mutagenesis and translesion synthesis, believed to be related to the differential activity of the two drugs (oxaliplatin is used, in combination with 5-fluorouracil, for the treatment of colorectal cancers against which cisplatin is inactive). The evaluation of the structural details of the platinum-DNA adducts and of their effects on protein, recognition can therefore help to understand why the biological activities of two similar platinum compounds (e.g., cisplatin versus oxaliplatin) are different. So far only nine cisplatin-DNA adducts have been characterized by NMR and/or x-ray crystallography. These structures were extensively reviewed by Ano et al. and found to be basically similar in structure. The cisplatin-GG adduct kinks the double helix approx. Approximately 60 towards the major groove and induces N sugar pucker for

gen binding properties of the Pt-DNA adduct and the DNA conformation.

**8. Sequence specific structural perturbation**

*Assumed mechanism for the formation of cisplatin-DNA adducts.*

X of 5′ XG\*, 5′ G\* and the C complementary to 3′ G\* [18].

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**Figure 7.**

Mitomycin-C is a well-characterized antitumor antibiotic that forms a covalent interaction with DNA after reductive activation (**Figure 8**). The activated antibiotic forms a cross-linking structure between guanine bases on adjacent strands of DNA therefore inhibiting single strand formation [8].
