Investigations of the kinetics and mechanism of reduction of a carboplatin pt(IV) prodrug by the major small-molecule reductants in human plasma
(2019) In International Journal of Molecular Sciences 20(22).- Abstract
The development of Pt(IV) anticancer prodrugs to overcome the detrimental side effects of Pt(II)-based anticancer drugs is of current interest. The kinetics and reaction mechanisms of the reductive activation of the carboplatin Pt(IV) prodrug cis,trans-[Pt(cbdca)(NH3)2Cl2] (cbdca = cyclobutane-1,1-dicarboxylate) by the major small-molecule reductants in human plasma were analyzed in this work. The reductants included ascorbate (Asc), the thiol-containing molecules L-cysteine (Cys), DL-homocysteine (Hcy), and glutathione (GSH), and the dipeptide Cys–Gly. Overall second-order kinetics were established in all cases. At the physiological pH of 7.4, the observed second-order rate constants k′... (More)
The development of Pt(IV) anticancer prodrugs to overcome the detrimental side effects of Pt(II)-based anticancer drugs is of current interest. The kinetics and reaction mechanisms of the reductive activation of the carboplatin Pt(IV) prodrug cis,trans-[Pt(cbdca)(NH3)2Cl2] (cbdca = cyclobutane-1,1-dicarboxylate) by the major small-molecule reductants in human plasma were analyzed in this work. The reductants included ascorbate (Asc), the thiol-containing molecules L-cysteine (Cys), DL-homocysteine (Hcy), and glutathione (GSH), and the dipeptide Cys–Gly. Overall second-order kinetics were established in all cases. At the physiological pH of 7.4, the observed second-order rate constants k′ followed the order Asc << Cys–Gly ~ Hcy < GSH < Cys. This reactivity order together with the abundances of the reductants in human plasma indicated Cys as the major small-molecule reductant in vivo, followed by GSH and ascorbate, whereas Hcy is much less important. In the cases of Cys and GSH, detailed reaction mechanisms and the reactivity of the various protolytic species at physiological pH were derived. The rate constants of the rate-determining steps were evaluated, allowing the construction of reactivity-versus-pH distribution diagrams for Cys and GSH. The diagrams unraveled that species III of Cys (−SCH2CH(NH3 +)COO−) and species IV of GSH (−OOCCH(NH3 +)CH2CH2CONHCH(CH2S−)-CONHCH2COO−) were exclusively dominant in the reduction process. These two species are anticipated to be of pivotal importance in the reduction of other types of Pt(IV) prodrugs as well.
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- author
- Liu, Yang ; Tian, Hongwu ; Xu, Liyao ; Zhou, Li ; Wang, Jinhu ; Xu, Benyan ; Liu, Chunli ; Elding, Lars I. LU and Shi, Tiesheng LU
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Kinetics, Reaction Mechanism, Platinum(IV) prodrug, Small-molecular reductants, Human plasmanism, Platinum(IV) prodrug, Small-Molecular reductants, Human plasma, platinum(IV) prodrug, Human Plasma, reduction, small-molecular reductants
- in
- International Journal of Molecular Sciences
- volume
- 20
- issue
- 22
- article number
- 5660
- publisher
- MDPI AG
- external identifiers
-
- scopus:85074879592
- pmid:31726728
- ISSN
- 1422-0067
- DOI
- 10.3390/ijms20225660
- language
- English
- LU publication?
- yes
- id
- ec8e3988-f732-48fa-8a75-2cea46914c4d
- date added to LUP
- 2019-11-20 15:01:48
- date last changed
- 2024-05-15 02:02:49
@article{ec8e3988-f732-48fa-8a75-2cea46914c4d,
abstract = {{<p>The development of Pt(IV) anticancer prodrugs to overcome the detrimental side effects of Pt(II)-based anticancer drugs is of current interest. The kinetics and reaction mechanisms of the reductive activation of the carboplatin Pt(IV) prodrug cis,trans-[Pt(cbdca)(NH<sub>3</sub>)<sub>2</sub>Cl<sub>2</sub>] (cbdca = cyclobutane-1,1-dicarboxylate) by the major small-molecule reductants in human plasma were analyzed in this work. The reductants included ascorbate (Asc), the thiol-containing molecules L-cysteine (Cys), DL-homocysteine (Hcy), and glutathione (GSH), and the dipeptide Cys–Gly. Overall second-order kinetics were established in all cases. At the physiological pH of 7.4, the observed second-order rate constants k<sup>′</sup> followed the order Asc << Cys–Gly ~ Hcy < GSH < Cys. This reactivity order together with the abundances of the reductants in human plasma indicated Cys as the major small-molecule reductant in vivo, followed by GSH and ascorbate, whereas Hcy is much less important. In the cases of Cys and GSH, detailed reaction mechanisms and the reactivity of the various protolytic species at physiological pH were derived. The rate constants of the rate-determining steps were evaluated, allowing the construction of reactivity-versus-pH distribution diagrams for Cys and GSH. The diagrams unraveled that species III of Cys (<sup>−</sup>SCH<sub>2</sub>CH(NH<sub>3</sub> <sup>+</sup>)COO<sup>−</sup>) and species IV of GSH (<sup>−</sup>OOCCH(NH<sub>3</sub> <sup>+</sup>)CH<sub>2</sub>CH<sub>2</sub>CONHCH(CH<sub>2</sub>S<sup>−</sup>)-CONHCH<sub>2</sub>COO<sup>−</sup>) were exclusively dominant in the reduction process. These two species are anticipated to be of pivotal importance in the reduction of other types of Pt(IV) prodrugs as well.</p>}},
author = {{Liu, Yang and Tian, Hongwu and Xu, Liyao and Zhou, Li and Wang, Jinhu and Xu, Benyan and Liu, Chunli and Elding, Lars I. and Shi, Tiesheng}},
issn = {{1422-0067}},
keywords = {{Kinetics, Reaction Mechanism, Platinum(IV) prodrug, Small-molecular reductants, Human plasmanism, Platinum(IV) prodrug, Small-Molecular reductants, Human plasma; platinum(IV) prodrug; Human Plasma; reduction; small-molecular reductants}},
language = {{eng}},
number = {{22}},
publisher = {{MDPI AG}},
series = {{International Journal of Molecular Sciences}},
title = {{Investigations of the kinetics and mechanism of reduction of a carboplatin pt(IV) prodrug by the major small-molecule reductants in human plasma}},
url = {{http://dx.doi.org/10.3390/ijms20225660}},
doi = {{10.3390/ijms20225660}},
volume = {{20}},
year = {{2019}},
}