Kinetic characterization of the interactions of trans-dichloro-platinum(IV) anticancer prodrugs and a model compound with thiosulfate

Dong, Jingran; Huo, Shuying; Song, Chao; Shen, Shigang; Ren, Yiwei; Shi, Tiesheng

doi:10.1007/s11243-013-9781-x

Cited by 12 publications

(9 citation statements)

References 24 publications

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“…As a matter of fact, some clean activation parameters have been obtained for the reduction of Pt(IV) compounds by other reductants such as L-methionine, 55 L-selenomethionine, 40 and thiosulfate. 57 However, when Asc and the thiol-containing compounds are used as reductants, clean activation parameters are difficult to get because their k′-pH profiles are all similar to those shown in Fig. 6.…”

Section: Re-examination Of the Isokinetic Relationshipmentioning

confidence: 92%

Reduction of ormaplatin and cis-diamminetetrachloroplatinum(iv) by ascorbic acid and dominant thiols in human plasma: kinetic and mechanistic analyses

et al. 2016

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The reductions of Pt(iv) anticancer prodrugs [Pt(dach)Cl4] (ormaplatin/tetraplatin), cis-[Pt(NH3)2Cl4], and cis,cis,trans-[Pt(NH3)2Cl2Br2] by the several dominant reductants in human plasma have been characterized kinetically in this work, including l-ascorbic acid (Asc), l-glutathione (GSH), l-cysteine (Cys), dl-homocysteine (Hcy), and a dipeptide Gly-Cys. All the reductions follow an overall second-order kinetics, being first-order each in [Pt(iv)] and in the [reductant]. A general reactivity trend of Asc < Hcy < Cys-Gly < GSH < Cys is clearly revealed for the reductions of [Pt(dach)Cl4] and [Pt(NH3)2Cl4] at 37.0 °C and pH 7.40. Analysis of the observed second-order rate constants k' implies that these Pt(iv) prodrugs have a very short lifetime (less than a minute) in human plasma and can hardly enter into cells before reduction and that Asc might not play a dominant role in the reduction process among the reductants. The reductions of [Pt(dach)Cl4] and [Pt(NH3)2Cl4] by Asc have been studied in a wide pH range, and a reaction mechanism has been proposed involving parallel reductions of the Pt(iv) complexes by the Asc protolytic species. Moreover, a halide-bridged (inner-sphere) electron transfer mode for the rate-determining steps is discussed in detail; several lines of evidence strongly bolster this type of electron transfer. Furthermore, the observed activation parameters corresponding to k' have been measured around pH 7.40. Analysis of the established k'-pH profiles indicates that k' is a composite of at least three parameters in the pH range of 5.74-7.40 and the measured activation parameters in this range do not correspond to a single rate-determining step. Consequently, the isokinetic relationship reported previously using the measured ΔH(‡) and ΔS(‡) in the above pH range might be an artifact since the relationship is not justified anymore when our new data are added.

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Section: Re-examination Of the Isokinetic Relationshipmentioning

confidence: 92%

Reduction of ormaplatin and cis-diamminetetrachloroplatinum(iv) by ascorbic acid and dominant thiols in human plasma: kinetic and mechanistic analyses

et al. 2016

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“…1a, where the absorbance of Hcy is negligible. The kinetic trace is clearly biphasic and can be interpreted in terms of two consecutive reactions [24]; the rapid initial decrease in absorbance (displayed in Fig. 1b after expansion) is attributed to the reduction of trans-[Pt(NH 3 ) 2 Cl 4 ] to its Pt(II) counterpart trans-[Pt(NH 3 ) 2 Cl 2 ].…”

Section: Kinetic Tracesmentioning

confidence: 96%

“…1b after expansion) is attributed to the reduction of trans-[Pt(NH 3 ) 2 Cl 4 ] to its Pt(II) counterpart trans-[Pt(NH 3 ) 2 Cl 2 ]. The relatively slow increase in the absorbance is ascribed to the substitution of one of the chloride ligands in trans-[Pt(NH 3 ) 2 Cl 2 ] by the excess Hcy in the reaction mixture [24]. These two consecutive reactions have well-separated timescales.…”

Section: Kinetic Tracesmentioning

confidence: 99%

Characterization of the mechanism of reduction of trans-diamminetetrachloroplatinum(IV) by l-cysteine and dl-homocysteine

Dong

Nan

et al. 2015

Transition Met Chem

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The interactions between Pt(IV) anticancer prodrugs incorporating two ammines/amines in trans positions in their equatorial planes and some important thiols have not been exploited to date. In this work, the reduction of one such Pt(IV) prodrug, namely trans-[Pt(NH 3 ) 2 Cl 4 ], by two thiol-containing amino acids L-cysteine (Cys) and DL-homocysteine (Hcy) which are prevalent in human plasma has been characterized by stopped-flow spectroscopic and ESI high-resolution mass spectral methods. The reduction process obeys overall second-order kinetics. The dependencies of the observed second-order rate constants k 0 on pH have been established between pH 4.03 and 11.24. Mass spectral analysis indicates that cystine and homocystine are the dominant products for the Cys and Hcy oxidations, respectively. The suggested reaction mechanism involves all possible protolytic species of Cys/Hcy, which attack one of the two apically coordinated chlorides in parallel (all as rate-determining steps), leading to a Cl ? transfer to the attacking sulfur atom. The rate expression has been derived, and the rate constants for the rate-determining steps have been calculated. Features of the reduction process are discussed based on the obtained rate constants. The overall kinetic and mechanistic picture enables an in-depth understanding of the reduction process of this type of Pt(IV) anticancer prodrug.

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“…The reductive elimination reactions of trans-dihalidoPt(IV) complexes involving various reductants have been interpreted to proceed via a halide-bridged electron transfer by use one of the two axially coordinated halides in the platinum(IV) complexes [46][47][48][49][50][51][52]. When the sulfur in NAC attacks the coordinated chlorides, a bridge between Cl and S atoms is formed, whereas the bonds of Cl-Pt-Cl are partially broken concurrently.…”

Section: Possible Transition States Of Rate-determining Stepsmentioning

confidence: 99%

“…transfer to the attacking sulfur atom and to formation of the three intermediates (1)-(3) depicted in Scheme 2. This type of electron transfer mode implies that in similar molecules, a better bridging atom will give rise to a faster rate [46][47][48][49][50][51][52]. We recently observed that the reduction of trans-[PtCl 2 (CN) 4 ] 2-by L-selenomethionine is 37,000 times faster than by L-methionine [24].…”

Section: Possible Transition States Of Rate-determining Stepsmentioning

confidence: 99%

A kinetic analysis of oxidation of the antioxidant N-acetyl-l-cysteine (NAC) by Pt(IV) complexes

You

Ren

Huo

et al. 2016

Transition Met Chem

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N-acetyl-L-cysteine (NAC) is an antioxidant and a supplement and has been demonstrated to have protective effects for a variety of toxic effects of heavy metals. Although previous works have shown that NAC can ameliorate the severe toxic effects of cisplatin, there is a lack of understanding of the interactions between NAC and Pt(IV)-based prodrugs. In this work, the oxidation of NAC by a cisplatin prodrug (cis-[Pt(NH 3 ) 2 Cl 4 ]), by a prototype of Pt(IV) anticancer drug ormaplatin ([Pt (dach)Cl 4 ]) and by a model compound (trans-[PtCl 2 (CN) 4 ] 2-) was characterized in detail. NAC was oxidized to NAC-disulfide as identified by mass spectrometric analysis. Time-resolved spectral and stopped-flow kinetic measurements were carried out over a wide pH range, demonstrating that the oxidation followed overall secondorder kinetics. The observed second-order rate constants k 0 versus pH profiles were established. A reaction mechanism was deduced, involving three parallel rate-determining steps; conceivable transition states were also proposed for these steps. Rate constants of the rate-determining steps, obtained from the simulations of rate equation to the k 0 -pH profiles, were largely correlated with the electron density on the sulfur atom in NAC. The Pt(IV) prodrugs can execute oxidative stress in the biological systems of the human body by direct oxidation of relevant molecules, similar to HOCl/OCl -and chloroamines. Instead, the oxidative stress involved in the severe toxic effects of cisplatin is produced via a different mode. NAC could be a chemoprotecting agent also for the Pt(IV) anticancer drugs if recent drug delivery technologies are used.

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Kinetic characterization of the interactions of trans-dichloro-platinum(IV) anticancer prodrugs and a model compound with thiosulfate

Cited by 12 publications

References 24 publications

Reduction of ormaplatin and cis-diamminetetrachloroplatinum(iv) by ascorbic acid and dominant thiols in human plasma: kinetic and mechanistic analyses

Reduction of ormaplatin and cis-diamminetetrachloroplatinum(iv) by ascorbic acid and dominant thiols in human plasma: kinetic and mechanistic analyses

Characterization of the mechanism of reduction of trans-diamminetetrachloroplatinum(IV) by l-cysteine and dl-homocysteine

A kinetic analysis of oxidation of the antioxidant N-acetyl-l-cysteine (NAC) by Pt(IV) complexes

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