Cis and trans ddp binding sites on dna although pt

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cis- and trans-DDP binding sites on DNA. Although Pt-DNA linkages are, generally speaking, kinetically inert, some- times a particular adduct will rearrange into a more stable linkage isomer. One interesting example is the product of the reaction of trans-DDP with the dode- canucleotide 5' -d(TCTACGCGTTCT). 79 Initially the platinum coordinates to the two guanosine residues, forming a trans-[Pt(NH 3 h{d(GCG)}] 1,3-intrastrand crosslink. This complex rearranges to a more stable trans-[Pt(NH 3 h{d(CGCG)}] 1,4-intrastrand crosslink with a half-life of 129 h at 30°C or 3.6 h at 62°C. In this rearrangement product the platinum is coordinated to a cytosine and a guan- osine residue. As just described, the binding of bifunctional platinum complexes to DNA proceeds in a stepwise fashion. The second step is sufficiently slow (a few hours), however, that various reagents such as NH 3 , nucleobases, and low con- centrations of thiourea can coordinate to the fourth site and trap the monoad- ducts. Generally speaking, however, given sufficient time both cis- and trans- DDP will bind DNA in a bifunctional manner. As such, they bear some resem- blance to organic alkylating agents, such as the nitrogen mustards, which have been employed as anticancer agents. 80 b. Crosslinking Reactions of Platinum Complexes There are three broad classes of DNA adducts that can be made by bifunctional platinum complexes. As illustrated for cis-DDP in Figure 9.10, they are DNA-protein crosslinks, interstrand DNA-DNA crosslinks, and intrastrand crosslinks,81 A fourth possi- bility for platinum complexes is bidentate chelate ring formation utilizing two donor atoms on a nucleotide. For many years, a favored such postulated mode of binding was chelation by the N7 -06 positions of the guanine base (Figure 9.9), since this structure could be formed only by cis- and not by trans-DDp.82,83
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interstrand crosslink intrastrand crosslink 539 DNA-protein crosslink bifunctional binding to guanine Figure 9.10 Possible bifunctional binding modes of cis-DDP with DNA (reproduced by permission from Reference 81). Such a structure has never been observed for cis-DDP binding to DNA, how- ever. DNA-protein and interstrand crosslinks formed by platinum complexes have been the focus of many attempts to explain cytotoxicity and antitumor behavior. 84 The technique of alkaline elution, in which crosslinked DNA-DNA strands or DNA-protein molecules bind to filter paper following denaturation under basic conditions, sensitively and easily reveals such adducts. trans-DDP forms such adducts more rapidly than the cis isomer, perhaps because of its faster chloride-ion hydrolysis rates (see above) and a more favorable geometry, but they also seem to be repaired more rapidly in cells. As will be shown, interstrand and DNA-protein crosslinks are a small minority of adducts formed by cisplatin, and their contribution to the cytotoxic and anticancer properties of
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540 9 / METALS IN MEDICINE the drug remains to be established. In studies of SV40 replication in vivo, DNA- protein crosslinking by cis- and trans-DDP
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