Intrastrand cross-linking

Models for the Interaction of cis-platin and its hydrolysis products with DNA are discussed. The models are the interstrand cross-link, intrastrand cross-link, N7-06 clip, platinum dimer interaction, Eichhorn costacking, and N1 pK shift. Interactions observed in model compounds have been observed to occur in DNA for most of the models, but it is not possible to say which, if any, is the important lesion in the anti-cancer action of cis-platin. 

Binding of cisplatin to the neighbouring bases in the DNA disrupts the orderly stacking of the purine bases when it forms a 1,2-intrastrand crosslink, it bends the DNA helix by some 34° towards the major groove and unwinds the helix by 13°. These cross-links are believed to block DNA replication. 

There are examples in which base radicals undergo reaction with adjacent base residues. The 5-(2 -deoxyuridinyl)methyl radical (63, Scheme 8.30) can forge an intrastrand cross-link with adjacent purine residues. Cross-link formation is favored with a guanine residue on the 5 -side of the pyrimidine radical and occurs under low-oxygen conditions. A mechanism was not proposed for this process, but presumably the reaction involves addition of the nucleobase alkyl radical to the C8-position of the adjacent purine residue. Molecular oxygen likely inhibits crosslink formation by trapping the radical 63, as shown in Scheme 8.24. The radical intermediate 89 must undergo oxidation to yield the final cross-linked product 90,... 

Hambley and co-workers have reported the synthesis, DNA cross-linking, and in vitro anticancer properties of a platinum(II) complex that was designed to bind the macromolecule in an interstrand rather than intrastrand manner,162 the latter being the dominant mode of DNA-binding by platinum anticancer drugs such as cisplatin. The complex [PtCl2(hpip)] ((46) ... 

The interstrand cross-link also induces DNA bending.72 X-ray and NMR studies on this adduct show that platinum is located in the minor groove and the cytosines of the d(GC) base pair involved in interstrand cross-link formation are flipped out of the helix stack and a localized Z-form DNA is observed.83-85 This is a highly unusual structure and very distorting—implications for differential repair of the two adducts have been addressed. Alternatively, the interstrand cross-link of the antitumor inactive trans-DDP is formed between a guanine (G) and its complementary cytosine (C) on the same base p a i r.86,87/ nms- D D P is sterically incapable of producing 1,2-intrastrand adducts and this feature has been cited as a dominant structural reason for its lack of antitumor efficacy. It is clear that the structural distortions induced on the DNA are very different and likely to induce distinctly different biological consequences. 

B-DNA 1,2-Intrastrand cross-link 1,2-Interstrand cross-link... 

The polynuclear platinum compounds stand in vivid contrast to mononuclear platinum complexes because the predominant DNA lesions are long-range inter- and intrastrand cross-links where the sites of platination may be separated by up to four base pairs. The consequent structural and conformational changes in DNA are also distinct. 

Aliosman, F., Caughlan, J., and Gray, G.S. (1989) Diseased DNA intrastrand cross-linking and cytotoxicity induced in human brain tumor cells by 1,3-fcis(2-chlorocthyl)-1 -nitrosourea after in vitro reaction with glutathione. Cancer Res. 49, 5954. 

In addition to intrastrand cross-link described above, ds-DDP can also form an interstrand cross-link representing less than 10% of the total lesions [8,74]. The NMR solution structure of the duplex d(CCTCG CTCTC)-d(GAGAG CGAGG) containing a single inter-... 

Figure 7.8 Modeled 1,4 interstrand and 1,5 intrastrand cross-links formed by platinum bifunctional compound BBR3464.

Although relatively few structural studies of the interstrand GG adduct [42, 45, 46] have been reported, the data presented reveal the structural distortion to be significantly different from that of the intrastrand adduct. The prime feature of this adduct is the cross-linking between the two strands at GC sequences, thereby causing a kink in the double helix. In this instance, however, the kink is towards the minor groove, with a value of -47° (Fig. 4.3). Another feature of this adduct not present in the other intrastrand adducts is the complementary cytosine bases extruding from the lesion site. 

The isomerization of the 1,2-intrastrand cross-link ds- Pt(NH3)2 -d(CCTG G TCC) d(GGACCAGG) to the 1,5-interstrand cross-link d(CCTG GTCC) d(GGACCAGG ) is also induced by chloride ions, which shows that even Pt-N7 bonds in Pt-l,2-GpG cross-links can be destabilized (67). 

Both Ru(II) and Ru(III) complexes are known to bind DNA preferentially at N7 of G but also to A and C bases (182, 183). Although most ruthenium antitumor agents have two reactive coordination sites, GG intrastrand cross-links on DNA do not appear to form readily. The only example appears to be the adduct of 27 with GpG, which has been structurally characterized by NMR spectroscopy (184). In this complex, the two N7-coordinated guanines adopt a head-to-head conformation and the two bases are strongly destacked. 

If a DNA adduct involves the nitrogen or oxygen atoms involved in base-pairing, and the adducted DNA is not repaired, base substitution can result. Adducts can be small, such as the simple addition of methyl or ethyl groups, or they can be very bulky, owing to reaction with multiringed structures. The most vulnerable base is guanine, which can form adducts at several of its atoms (e.g., N7, C8, O6 and exocyclic N2) (Venitt and Parry, 1984). Adducts can form links between adjacent bases on the same strand (intrastrand cross-links) and can form interstrand crosslinks between each strand of double-stranded DNA. 

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