Metals in medicine
Metals in medicine

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Metals in medicine

5.3 Platinum binding to DNA

Oligonucleotides are short sections of DNA (2 to 15 nucleotides long) used for model studies. They are often referred to as a ‘duplex’ in recognition of the two-stranded helical structure of DNA.

The early structural characterisation of oligonucleotide-bound cisplatin was done using X-ray crystallography, cap h one postfix times cap n times cap m times cap r and molecular modelling. Cisplatin was found to form a cis complex with two adjacent guanines on the same strand (known as a G(N7)–p–G(N7) linkage, often shortened to G–p–G or G–G). This is shown in Figure 19.

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Figure 19  NMR structure of the DNA duplex dodecamer d(CCTCTG*G*TCTCC). d(GGAGACCAGAGG), containing the cisplatin (GpG–N7(1), N7(2)) 1,2-intrastrand cross-link at the position of the asterisks (pdb 1A84 [Tip: hold Ctrl and click a link to open it in a new tab. (Hide tip)] ; Gelasco and Lippard, 1998).
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Experiments found that cisplatin formed several different types of adduct with the DNA oligomers.

The major product (60–65%) is the G–G 1,2-intrastrand link between guanine residues which reside in the major groove in the B-form DNA (also shown in Figure 20): cis-[Pt(NH3)2(G–p–G)] (Structure 6).

Smaller quantities of other adducts include:

  • 20–25% of a G–A 1,2-intrastrand: cis-[Pt(NH3)2(A–p–G)], (Structure 7).
    Structure 6 (left) and 7 (right)
  • 5–10% of more widely spaced guanine adducts: the 1,3-intrastrand and G–p–G interstrand complexes (Structure 8, 9 and Figure 20). (Note: N in Structure 8 represents another base.) In the latter, cisplatin forms a cross-link between the two strands.
    Structure 8 (left) and 9 (right)
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Figure 20  NMR solution structure of the short duplex [d(CAT–AG*CTATG)]2 cross-linked at the position of the asterisk which here is doubled to represent guanine bases on two strands (pdb 1DDP; Huang et al., 1995).
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  • 2–5% of a monoadduct (Structure 10), and < 1% of DNA–protein binding (Structure 11).
    Structure 10 (left) and 11 (right)
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