Interstrand cross-linking

Interstrand cross-link Interstrand cross-link... 

Although the majority of adducts formed by platinum on DNA are intrastrand cross-links, interstrand cross-linking also occurs both in vitro (33, 40) and in vivo (122, 134, 135). Estimates of the frequency of formation of interstrand cross-links range from 1-7% (33, 54, 108). Although... 

A logical place, therefore, to begin to examine for the structural origin of differential effects between mononuclear and polynuclear platinum complexes is in the structures of interstrand cross-links. Interstrand cross-linking of poly(dG-dC).poly(dG-dC) by cw-DDP does not cause a B -> Z transition. The inter-... 

The only prominent antitumor tetravalent platinum complex so far is iproplatin (102). In vitro it has been shown to cause interstrand DNA-breaking and cross linking. Free radical scavengers inhibit these effects. The complex is less neurotoxic and less nephrotoxic than cisplatin. Its synthesis begins with hydrogen peroxide oxidation of cis-dichlorobis(isopropvlamine) platinum (100) to the dimethylacetamide complex 101. The latter is heated in vacuum to liberate iproplatin [25]. 

No cross-linking was observed when noncomplementary rather than complementary DNA was added to the mixture, and thus interstrand transfer of QM appears to be effective only from within a hybridized complex. Despite the obvious complications of annealing DNA that is constrained by capture of both QM equivalents of QMP11, such a species is suggested since both QM sites require protection from irreversible reaction over the many hours in which the cross-linking activity is preserved. 

Lee, C.-S. Gibson, N. W. DNA interstrand cross-links induced by the cyclopropylpyrro-loindole antitumor agent bizelesin are reversible upon exposure to alkali. Biochemistry 1993, 32, 9108-9144. 

Platinum analogs Produce intra- and interstrand cross-links and DNA adducts to disrupt DNA replication Taxane agents Stabilize microtubules and prevent de-polymerization of tubulin... 

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) ... 

Figure 2 Double-stranded oligonucleotide photoprobes that simulate modified DNA and intended to cross-link to DNA-binding proteins. (A) Probe modeling interstrand cross-linking by cisplatin Source From Ref. [63], with permission from the American Chemical Society via the Rightslink service (license number 2458870278307 granted June 30, 2010). The benzophenone probe prior to reaction with DNA is shown in the lower part of the panel. (B) Photoaffinity probe for bacterial DNA repair proteins. TT is a simulated thymine dimer intended to be recognized as a site of damage in DNA, and T (two instances) is the diazirine thymine derivative T Source From Ref. [64], with permission from Wiley.

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... 

In the case of complexes such as (21) and (23) which have an extended planar ligand, a significantly higher proportion of interstrand cross-links in DNA is formed in comparison to either cis- or trans-platin.172 The steric effects of these planar ligands result in the formation of structurally unique 1,2-interstrand cross-links like those formed by cisplatin, a unique example of how steric effects may alter a nonactive lesion into an active one (Figure 13).173,174 Model studies predicted this outcome by preparation of the monofunctional models trans-[PtCl(9-ethylguanine) (NH3)(quinoline)] and comparison of substitution rates of the Pt—Cl bond by G or C mononucleotides.175 176 Interestingly, the iminoether compound (25) appears to form predominantly monofunctional adducts with DNA.177... 

Figure 13 Interstrand cross-links formed by sterically hindered rraw,s-platinum compounds.

Ewig, R.A.C., and Kohn, K.W. (1977) DNA - protein cross-linking and DNA interstrand cross-linking by haloethylnitrosoureas in L1210 cells. Cancer Res. 38, 3197. 

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-... 

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