Adenine 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. 

Fig. 4.8 The first substitution reactions between activated cisplatin and adenine.

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. 

When GBG sequences are present in an oligonucleotide, cisplatin chelates also to both guanines when the central base is adenine then also an AG chelate is formed. 

Rubin et al.106, by soaking their crystals with cisplatin, found only monofunctional binding at certain guanine-N7 sites. After soaking with the trans isomer, the same binding was found, but also binding at adenine-N7. 

Fig. 1. Two ribbon representations of the crystal structure of the DNA decamer d(CCTCG -CTCTC/GAGAG CGAGG) containing a unique cisplatin interstrand cross-link at d(GpC)-d(GpC) site (asterisks indicate the chelated bases in the adduct). A front view (A) allows to see the structure with the lesion in the minor groove. A side view (B) shows the chicane of the backbone with the helix-sense reversal. Ptn atom, yellow ammine groups, navy blue sugars, pink guanines, navy blue adenines, red thymines, yellow cytosines, hght blue phosphodiester backbone, green.

Pt-DNA Adducts are widely believed to be responsible for the antitumor activity of cisplatin (ci5,-PtCl2(NH3)2) (Fig. 1) and have been studied for many years. In competition reactions at low Pt/nucleotide concentrations, cisplatin was shown to bind to the N(7) position of guanine (G = AY7)-platinatcd G or G derivative) and, to a lesser extent, of adenine (A)... 

The preferential binding of the antitumour drug cisplatin (ds-diamminechloroplatinum-II) to GpG and ApG sequences in DNA has prompted the use of ab initio calculations with relativistic pseudopotentials to evaluate three important parameters for the Pt-adenine model complex [Pt(NH3)3 adenine]. These are the force constant for the Pt—N-7 bond bending out of the adenine... 

Pt-bridges in various single-strand and double-helix DNA sequences. DFT and MP2 study of the cisplatin coordination with guanine, adenine, and cytosine ... 

More valuable information on nucleic acids has been obtained from pyrolysis data when it was possible to evaluate the nature and abundance of the purine/pyrimidine bases. The information on these bases is important for monitoring in vitro DNA synthesis [5,6], for the evaluation of chromosome modifications [7], and for the study of complex formation of DNA with cisplatin [11,12]. As indicated previously, the DIP technique was reported to be more useful for detecting the base component of the nucleic acid. However, some information on the bases can be obtained also by Curie point Py-MS, as it can be seen from the spectrum of NADPH (nicotinamide adenine dinucleotide phosphate) shown in Figure 13.2.3. The spectrum was obtained in similar conditions as spectra for DNA and RNA shown previously [8]. 

Competitive effects for the interactions of cisplatin with various active sites in the cellular environment are discussed in papers of Deubel.55,56 In the earlier paper, energetic and structural data of complexes with the different substituted ligands were explored. The more recent work deals with kinetic factors in the relation to the transition state (TS) for water replacement of the semihydrated cisplatin complex (cis-[Pt(NH3)2(H20)Cl]+ ) with either an N- or S-containing ligand (thiopheneimidazol, dimethyl sulphide, or methanethiolate which serve as amino acid models). Deubel concluded the kinetic preference of N-sites over S-nucleophiles where the important role is played by the electrostatic terms. In addition, the aliphatic/aromatic character of the substituent as well as the influence of different dielectric constants of the environment are very important. A more realistic model for the aqua-ligand replacement with adenine and guanine was studied in works of Chval et al.53,57 and Eriksson and coworkers.58 They performed independently the estimation of the thermodynamic and kinetic parameters of this process. 

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