Methionine cisplatin

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.

Sulfur-bound L-Met, as opposed to S,N-chelated L-Met, is more reactive as a ligand on Pt(II) and can be slowly replaced by N7 of G (95, 96). Transfer of Pt onto DNA via Met-containing peptides or proteins may therefore be possible. Monofunctional adducts of the type [Pt(en)(G)(L-Met-S)] appear to be very stable (97) and so methionine may play a role in trapping these adducts. Also, the high trans influence of S as a Pt(II) ligand can lead to the facile labilization of trans-am(m)ine ligands and this allows cisplatin to react with GMP faster in the presence of L-Met then in its absence (98), which introduces another route to DNA platination. 

It was early determined that in the cell, the electrophilic species derived from cisplatin bind to three major targets RNA (which is present at high concentration in cytoplasm, together with nucleoproteins) (50%), DNA (40%) and proteins (10%) [25]. It also binds to cysteine and methionine residues of proteins, to metallothioneins, glutathione, methionine, and glutamate which are good traps for chloro and/or aqua platinum electrophiles [26],... 

XH- and 195Pt-NMR investigations have shown that therapeutic nucleophilic agents for cisplatin, such as Na(ddtc) (sodium diethyldithiocarba-mate) and thiourea, can help to remove Pt from certain proteins [35]. The mechanism may be based on the relatively easy reversal of Pt binding to methionine side chains. In contrast, nephrotoxicity, thought to be caused by formation of Pt-cysteine adducts (Pt11 thiolate bonds), cannot be reversed by Na(ddtc) and thiouera. 

STS was shown to provide protection from nephrotoxicity when administered in a period between 1 h prior to and 0.5 h after cisplatin injection [36] [37]. It has been shown that protein-bound cisplatin cannot be released by STS [38] [39][40], although STS is able to break the Pt-thioether bond in methionine model systems [41], A likely explanation for its protecting effect is that STS is known to be concentrated extensively in the kidney, where... 

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-... 

In this respect it should be mentioned that Pt-methionine species are generally not antitumor active However, methionine is known to play an important role in the metabolism of cisplatin. The bischelate [Pt(Met-S,A02 has been isolated form the urine of patients treated with cisplatin [85]. On the other hand, intermolecular competition studies have shown that formation of a bifunctional G-N(7),G-N(7) adduct is possible for the cisplatin analog PtCl2(en)[19][86],... 

Thioethers form stable complexes, particularly if they are polydentate. Whereas only two sulfur atoms are coordinated in Ph2Pt(9S3),26 larger macrocycles, as in [Pt(12S4)]2+, can encapsulate the metal atom.27 The L-methionine complex (18-H-XII) is a metabolite of the anti-cancer drug cisplatin (see below).28... 

Stefanka, Z., Hann, S., Koellensperger, G., Stingeder, G. Investigation of the reaction of cisplatin with methionine in aqueous media using HPLC-ICP-DRCMS. J. Anal. At. Spectrom. 19, 894-898 (2004)... 

Heudi O., Mercier-Jobard S., Cailleux A., Allain R, Mechanisms of reaction of L methionine with carboplatin and oxaliplatin in different media A comparison with cisplatin, Biopharm. Drug Dispos., 20, 107-116,1999. 

In cisplatin treatment, bis(methionine)piatinum(II) complexes (4.16) are excreted in the urine. The general structural features required in Pt(II) complexes for anti-... 

A number of other agents, all sulfur nucleophiles, have been shown to inhibit cisplatin nephrotoxicity cuid the structures of a number of these are shown in Figure 2.2. The fact that sulfur compounds, such as thiosulfate [21], sulfiram and its metabolite diethyldithiocarbamate (DDTC) [22], thiourea (TU) and methionine [23], penicillamine [24], reduced glutathione [25], and the radioprotectant WR-2721 (5-2,3-aminopropylaminoethylphosphorothioic acid) [26] affect the nephrotoxicity is of importance mechanistically. Three of these compounds (thiosulfate, diethyldithiocarbamate, and WR-2721) are in clinical trials. The... 

Substitution of aqua ligands by nitrogen donors such as the nucleic acid bases leads to mono- and disubstituted complexes whose properties, of course, have been extensively studied (Chapter 4). Once inside the cell, however, only a small proportion of the platinum is complexed to the DNA. Metabolism of the platinum complexes therefore takes place with other biomolecules besides DNA. Amino acid reactions may take place which may sequester the complex. Further, in the case of substitution by nucleophiles with strong tram influence, especially those of sulfur, displacement of amine and deactivation may occur. Interestingly, amine labilization tram to a thioether in d5-[Pt(NH3)2(Me2S)2] has been observed [107]. In vivo, thioethers such as methionine could effect the same chemistry and the characterization of [Pt(methionine)2], assigned the structure as shown, as a metabolite of cisplatin [108] confirms this view ... 

At variance, a more classical chemical environment was found for the pla-tinum(II) center in the cisplatin-hen egg white lysozyme (HEWL) species (Figure 9.6B), where platinum was found to bind to the Ns of His 15 of HEWL, two ammonia molecules in the cisplatin and another one possibly to be loosely bound water molecule. No more significant modifications of the electron density map of the protein surface were observed, ruling out the presence of additional binding site, for example, the two methionine residues (Met-12... 

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