Guanine cisplatin

Tab. 4.3 Geometric data for adenine and guanine attack on the guanine-cisplatin mono adduct. The terms are defined in Fig. 4.4. 

Eloxatin ) (cisplatin) in that it binds to the N-7 position of guanine, which results in cross-linking of DNA and double-stranded DNA breaks. Acute (within first 2 days) and persistent (greater than 14 days) neuropathies Additional toxicites Anaphylactic-like reactions, dyspnea... 

Figure 2.5 The cisplatin reactive group can covalently couple to methionine-, cysteine-, and histidine-containing peptides or proteins. It also reacts with guanine groups to form a covalent modification on the N7 nitrogen.

Fig. 4.9 The first substitution reactions between activated cisplatin and guanine.

Cisplatin (Platinol) is an inorganic coordination complex with a broad range of antitumor activity. It is especially useful in the treatment of testicular and ovarian cancer. It binds to DNA at nucleophilic sites, such as the N7 and 06 of guanine, producing alterations in DNA structure and inhibition of DNA synthesis. Adjacent guanine residues on the same DNA strand are preferentially cross-linked. This platinating activity is analogous... 

The two guanines are no longer stacked, but the structure is impossible for the trans isomer. The cisplatin adducts appear to prevent proper DNA repair and to induce programmed cell death (apoptosis)/... 

There have been numerous studies of the interaction of the highly effective anticancer drug cisplatin, c/5-[Pt(NH3)2Cl2], with DNA. The majority of these studies have concentrated on the adduct formed between the platinum(II) ion and two adjacent guanine bases (G) on one strand of DNA this is the adduct most frequently... 

The observation that cisplatin forms adducts with the GpG and ApG (A - adenine p = phosphate) sequences of DNA but not with the GpA sequence has also been probed by molecular mechanics1209,2101. In this case it was found that there is a substantial dependence of the nature of the interactions of one of the ammine ligands from the base on the 3 side (the second in the sequence). When this base is guanine the interaction is a strong hydrogen bond but when it is adenine the interaction is a repulsive interaction between the same amine ligand and the exocyclic -NH2 group of the adenine. This is consistent with formation of the adducts with GpG and ApG and the nonformation of the adduct with GpA. 

Fig. 7. Schematic representation of cisplatin bonding to DNA. (1) monofunctional binding (X = Cr, OH", OH2) (2) interstrand crosslinking (3) protein-DNA crosslinking (4) intrastrand crosslinking between adjacent guanines (5) intrastrand crosslinking between two guanines separated by a third base (6) intrastrand crosslinking at a-AG-unit...

As will be shown in a later section, cisplatin shows a very strong preference for GG-sequences in DNA, i.e. a G in a GG sequence appears to have a preference above the other guanines. The reasons for this are still subject of debate, but may have something to do with a better approach of the cis-Pt group in an electrostatic manner. 

Knowing the strong preference of cisplatin for guanine-N7 binding, does chelation occur to two guanines separated by a third base ... 

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