Cisplatin reaction with

Pt- and 15N-NMR Spectroscopic Studies of Cisplatin Reactions with Biomolecules... 

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.

Glutathione readily replaces the GSMe on platinum in the reaction with [Pt(dien)(GSMe)]2+ (GSMe = S-methylglutathione) - this system is claimed to be an effective model for cisplatin-protein interaction 224). Rate constants and activation parameters have been... 

Intracellular thiolate ligands such as glutathione (GSH, the tripeptide y-L-Glu-L-Cys-Gly) are believed to inactivate cisplatin because the reactions with cisplatin tend to be irreversible (35). Elevated levels of GSH have been observed in cisplatin-resistant cells. Recently, it has been shown that an MRP gene, which encodes a human ATP-dependent glutathione S-conjugate export pump (GS-X pump), is expressed at higher levels in cisplatin-resistant (HL-60/R-CP) cells than in sensitive cells (36). The GS-X pump may contribute to the excretion of Pt-GS complexes from cells (37). 

In human plasma at 37°, the disappearance of cisplatin occurred with a tl/2 value of 1.3 h. Kinetics analysis demonstrated that the major components of reaction were formation of hydrated species (tl/2 3.4 h), irreversible binding to proteins (t1/2 2.1 h), and formation of mobile conjugates (e.g., with glutathione t1/2 24 h) [185], A very large quantity of relevant data are compiled in [181],... 

Direct reactions with DNA serve as the molecular basis for the action of several anti-tumor drugs. Cancer is primarily a disease of uncontrolled cell growth, and cell growth depends on DNA synthesis. Cancer cells are often more sensitive than normal cells to compounds that damage DNA. For example, the anti-tumor drug cisplatin reacts with guanine bases in DNA and the daunomycin antibiotics act by inserting into the DNA chain between base pairs. In either case, these biochemical events can lead to the death of a tumor cell. 

After thirty years of research, cisplatin has led to the discovery of several new generation anticancer drugs discussed in this book. Cisplatin has also become an outstanding tool to study all aspects of DNA properties, from reaction with small cationic species to interaction with proteins which induce biological signals triggering apoptosis. 

After administration, the drug circulates in the blood, primarily as the chloride (for cisplatin), or as another rather inert form (such as the biscar-boxylate in carboplatin). In the blood, also reactions with proteins and rescue agents can take place. Upon passing through cell walls (either actively or passively), intracellular reactions with peptides and proteins may take place, presumably followed by transfer to nucleic acids. Given the strong (kinetic) preference of Pt compounds to react with class-B donor atoms (such as those from thiolates and thioethers), binding to nucleic-acid bases (a thermodynamic end product) must at least occur partially via labile intermediates. 

Displacement of Pt-S-Bound L-Methionine by 5 -GMP. In an effort to understand why cisplatin reacts with 5 -GMP even in the presence of methionine, Barnham et al. [83] performed a competitive reaction experiment between [Pt(dien)Cl]Cl, L-methionine, and 5 -GMP. They observed that, in the first 40 hours of the reaction, the methionine was platinated to yield [Pt(dien)(Met-S )]2+, whereas only little of the 5 -GMP had reacted. In the latter stages of the reaction, this complex disappears as the platinum binds to 5 -GMP, resulting in the complex [Pt(dien)(5 -GMP, N(7))]2+ and free methionine. The kinetics of the displacement reaction were studied and the half-life of the reaction was determined to be 167 h at 310 K. The calculated 77 and. S values for this displacement reaction are indicative of a sub-... 

It has long been known that the products of the reaction of cisplatin (1) with glycinate are the chloride salt of 9, ds-[Pt(NH3)2(gly-A/,(9)]Cl, and, with excess glycinate, m-Pt(NH3)2(gly-A02 (13) [6] [7]. Pivcova etal. [8] [9] have shown that these products are obtained when 1 reacts with glycine under physiological conditions. The crystal structure of the N, O-chelate complex 9 has been determined [10]. 

Figure 13 Mechanism of action and competing cellular targets of cisplatin. Solid arrows delineate the normal progression to formation of DNA lesions and dashed arrows represent nonproductive, dead-end reactions with other substances...

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