Oxidation of 3,6-dioxa-1,8-octanedithiol by platinum(IV) anticancer prodrug and model complex: kinetic and mechanistic studies

The Journal of Physical Chemistry. B
Shuying HuoTiesheng Shi

Abstract

Thioredoxins are small redox proteins and have the active sites of Cys-Xaa-Yaa-Cys; they are overexpressed by many different cancer cells. Cisplatin and Pt(II) analogues could bind to the active sites and inhibit the activities of the proteins, as demonstrated by other researchers. Platinum(IV) anticancer drugs are often regarded as prodrugs, but their interactions with thioredoxins have not been studied. In this work, 3,6-dioxa-1,8-octanedithiol (dithiol) was chosen as a model compound for the active sites of thioredoxins, and its reactions with cis-[Pt(NH(3))(2)Cl(4)] and trans-[PtCl(2)(CN)(4)](2-) (cisplatin prodrug and a model complex) were studied. The pK(a) values for the dithiol were characterized to be 8.7 ± 0.2 and 9.6 ± 0.2 at 25.0 °C and an ionic strength of 1.0 M. The reaction kinetics was followed by a stopped-flow spectrophotometer over a wide pH range. An overall second-order rate law was established, -d[Pt(IV)]/dt = k'[Pt(IV)][dithiol], where k' stands for the observed second-order rate constants. Values of k' increased several orders of magnitude when the solution pH was increased from 3 to 9. A stoichiometry of Δ[Pt(IV)]/Δ[dithiol] = 1:1 derived for the reduction process and product analysis by mass spectromet...Continue Reading

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Citations

May 15, 2013·Journal of Inorganic Biochemistry·Shuying HuoTiesheng Shi
Jun 22, 2016·Dalton Transactions : an International Journal of Inorganic Chemistry·Jingran DongTiesheng Shi
Apr 4, 2018·Dalton Transactions : an International Journal of Inorganic Chemistry·Jingran DongLars I Elding
May 3, 2013·Chemical Communications : Chem Comm·Nicolas P E Barry, Peter J Sadler
Jul 31, 2014·Dalton Transactions : an International Journal of Inorganic Chemistry·Shuying HuoTiesheng Shi
Jan 23, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Changying SongShigang Shen
Jun 12, 2013·Chemical Communications : Chem Comm·Seowoo KimRichard J Puddephatt
Jan 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiaolai Zhang
Feb 11, 2014·Metallomics : Integrated Biometal Science·O PinatoC Sissi

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