Interstrand adduct

While the critical role of intrastrand 1,2-crosslinks in the mechanism of action of the anti-tumor drug cis- [PtCl2(NH3)2] is well established, much less is known about the few frans-analogs that exhibit similar efficacy. A series of 1,3-adducts has been characterized with 3-mers generally involving purine N7 coordination (32-34), and either monofunctional or interstrand adducts are formed with duplex DNA (35). However, one of the most active compounds, frans-[PtCl2 ( )-HN = C(OMe)Me 2], (2), has been shown to form a 1,2-adduct with 2-mer ribonucleotide sequence r(AG) (36). Though the formation of the... 

The distortion of the tertiary structure of DNA induced by cisplatin depends on which type of adduct is formed. Only two types of structures have been determined, either by means of X-ray crystallography or NMR - the GG intrastrand and interstrand adducts [42-44]. There is, however, good reason to believe that 5 -AG intrastrand adduct is structurally very similar to the GG counterpart. 

Brabec V. Chemistry and structural biology of 1,2-interstrand adducts of cisplatin. In (Kelland LR, Farrell N, eds) Platinum-Based Drugs in Cancer Therapy 2000 Humana Press Inc. Totowa, NJ pp. 37-61. 

Models of adducts that link one strand of DNA to the other (interstrand) have also been produced121 2121. These, too, reveal hydrogen bonding interactions consistent with established structure-activity relationships. The models have been used to aid in the design of new platinum(II) complexes that should form the interstrand adducts in preference to intrastrand adducts12151. 

Following activation via intracellular aquation reactions, cisplatin forms a variety of stable bifunctional adducts with DNA, as depicted in Figure 3. Cisplatin mainly forms 1,2-intrastrand cross-links on adjacent purine bases. It has been found that 60-65% of the platinum bound to DNA is in the form of l,2-d(GG) intrastrand cross-links and 20-25% in intrastrand l,2-d(AG) cross-links. Other adducts formed are the l,3-d(GXG) and l,4-d(GXXG) cross-links, accounting for at most 6%. Only a small percentage of cisplatin (1.5%) was found to be involved in interstrand adducts. It remains... 

Coordination of these platinum species to DNA occurs in two steps, with considerable sequence specificity. The first step involves formation of monofunctional adducts, primarily at the N7 position of guanine or adenine. These monofunctional Pt-DNA adducts react further to form bifunctional adducts, mainly at the N7 position of nearby guanines, and to a lesser extent, adenine. If the coordinated nucleotide bases are on the same strand of DNA, an intrastrand cross-link is formed. If platinum links two bases on opposite DNA strands, the result is an interstrand adduct. 

The relative amount of each adduct was determined by first treating DNA with cisplatin in vitro and then enzymatically degrading the DNA to nucleotides with DNase I and nuclease PI. The products were chroma-tographically separated and identified by their H NMR spectra (40). The relative proportions of adducts were cw-[Pt(NH3)2 d(GpG) ], 47-50%, cis-[Pt(NH3)2 d(ApG) ], 23-28% (intrastrand cross-links to adjacent bases), c -[Pt(NH3)2 d(GMP)2 ] 8-10% (the sum of intrastrand adducts between nonadjacent guanines and interstrand adducts), and [Pt(NH3)3 d(GMP) ]... 

The different possible adducts formed between mitomycin C and DNA have been isolated by degradation of DNA after in vitro alkylation/crosslinking reactions and structurally characterized. Monoadduct 21 (Scheme 11.3), derived from alkylation at C-l only [53], and monoadducts 22 [54] and 23 [55, 56] (derived from C-10 alkylation by 16 at N-7 or N-2 of guanine, respectively) have been isolated, together with bisadducts 24 [57] and 25 [58], derived from interstrand and intrastrand crosslinks, respectively, and adduct 26 [59], formed by addition of a molecule of water to C-10 instead of the second guanine. All of these adducts have also been isolated from DNA after in vivo crosslinking [60, 61]. 

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... 

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. 

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... 

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