Alterations in the binding of [Cl(NH3)5RuIII to DNA by glutathione:: Reduction, autoxidation, coordination, and decomposition

被引:71
作者
Frasca, DR [1 ]
Clarke, MJ [1 ]
机构
[1] Boston Coll, Merkert Chem Ctr, Chestnut Hill, MA 02467 USA
关键词
D O I
10.1021/ja991113p
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The autoxidation of glutathione (GSH) is catalyzed by [Cl(NH3)(5)Ru-III](2+) yielding only [OH(NH3)(5)Ru-III](2+) and GSSG according to the rate law d[GSSG]/dt = k[Ru][GSH], where k = 3 M-1 s(-1). The anaerobic reaction of GSH with [Cl(NH3)(5)Ru-III](2+) yields first [OH(NH3)(5)Ru-III](2+) and then [GS(NH3)(5)Ru-III](+) at neutral pH, both through redox catalysis. The reaction appears to proceed through reduction of Rum by GSH to give [H2O(NH3)(5)Ru-II](2+), followed by coordination to produce [GSH(NH3)(5)Ru-II](2+) and then oxidation of the latter ion by [OH(NH3)(5)Ru-III](2+) Or GSSG to yield [GS(NH3)(5)Ru-III](+). [GS(NH3)(5)Ru-III](+) is also produced by the reaction of GSH with [(NH3)(6)Ru](3+) or [py(NH3)(5)Ru](3+). Glutathione reduces [OH(NH3)(5)Ru-III](2+) through a pre-equilibrium mechanism according to the following rate law: d[Ru-II]/dt = k[Ru-III][GSH]/(K-i + [GSH]), where K-i = 2.0 x 10(-3) M-1 and k = 2.3 x 10(-3) s(-1). The reduction potential of [(GS)(NH3)(5)Ru-III] is pH-dependent according to the Nernstian equation: E = E degrees - 0.59 log {K-a/([H+] + K-a)}, where E degrees = -440 mV, pK(a) = 7.1. While [GS(NH3)(5)Ru-III] is stable for extended periods under inert atmosphere, it changes in air, eventually yielding [HO(NH3)(5)Ru-III] among other products at high pH with k(obs) (s(-1)) = (k(1)K(a) + k(2)[H+])/([H+] + K-a), where k(1) = 9 x 10(-6) s(-1), k(2) = 1.2 x 10(-4) s(-1) M-1, and pK(a) = 12. At [GSH]/[Ru-III] less than or equal to 1, the coordination of [Cl(NH3)(5)Ru-III](2+) to DNA. is facilitated by GSH reduction to the more substitution-labile [H2O(NH3)(5)Ru-II](2+). However, at [GSH]/[Ru-III] greater than or equal to 1, guanine binding on DNA is inhibited by GSH, which coordinates Ru-II and facilitates oxidation back to Ru-III because of the low E degrees of [GS(NH3)(5)Ru-III](+). Consistent with this is the increased toxicity of [Cl(NH3)(5)Ru-III](2+) to Jurkat T-cells, when GSH levels are suppressed. High [GSH]/[Ru] alters the DNA binding of [H2O(NH3)(5)Ru-II](2+) to essentially eliminate G(7) coordination and lower C-4 binding, but leaving A(6) binding relatively unaffected, which may have implications for the mechanism of ruthenium antitumor agents.
引用
收藏
页码:8523 / 8532
页数:10
相关论文
共 51 条
[21]   REACTIVITY OF CHLORO(DIETHYLENETRIAMINE)PLATINUM(II) AND AQUA(DIETHYLENETRIAMINE)PLATINUM(II) IONS WITH GLUTATHIONE, S-METHYLGLUTATHIONE, AND GUANOSINE 5'-MONOPHOSPHATE IN RELATION TO THE ANTITUMOR-ACTIVITY AND TOXICITY OF PLATINUM COMPLEXES [J].
DJURAN, MI ;
LEMPERS, ELM ;
REEDIJK, J .
INORGANIC CHEMISTRY, 1991, 30 (12) :2648-2652
[22]   GLUTATHIONE-MEDIATED ACTIVATION OF ANTICANCER PLATINUM(IV) COMPLEXES [J].
EASTMAN, A .
BIOCHEMICAL PHARMACOLOGY, 1987, 36 (23) :4177-4178
[23]  
ELDING LI, 1996, INORG CHEM, V35, P3498
[24]   SYNTHESIS AND PROPERTIES OF PENTAAMMINEPYRIDINERUTHENIUM(2) AND RELATED PENTAAMMINERULTHENIUM COMPLEXES OF AROMATIC NITROGEN HETEROCYCLES [J].
FORD, P ;
RUDD, DFP ;
GAUNDER, R ;
TAUBE, H .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1968, 90 (05) :1187-&
[25]  
FRANOLIC JD, 1996, 212 NAT M AM CHEM SO
[26]  
Frasca D, 1996, Met Based Drugs, V3, P197, DOI 10.1155/MBD.1996.197
[27]   OXIDATION OF THIOGLYCOLIC ACID AND GLUTATHIONE BY (TRANS-CYCLOHEXANE-1,2-DIAMINE-N,N,N',N'-TETRAACETATO)MANGANATE(III) IN AQUEOUS-MEDIA [J].
GANGOPADHYAY, S ;
ALI, M ;
DUTTA, A ;
BANERJEE, P .
JOURNAL OF THE CHEMICAL SOCIETY-DALTON TRANSACTIONS, 1994, (06) :841-845
[28]   AUTOXIDATION OF PENTAAMMINERUTHENIUM(III)-NUCLEOSIDE COMPLEXES - XANTHINE-OXIDASE ACTIVITY IN A SIMPLE COMPOUND WITHOUT OXO ATOM TRANSFER [J].
GARIEPY, KC ;
CURTIN, MA ;
CLARKE, MJ .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1989, 111 (13) :4947-4952
[29]   Imidazole release from the antitumor-active ruthenium complex imidazolium trans-tetrachlorobis (imidazole) ruthenate(III) by biologically occurring nucleophiles [J].
Hartmann, M ;
Lipponer, KG ;
Keppler, BK .
INORGANICA CHIMICA ACTA, 1998, 267 (01) :137-141
[30]   Reactions of [Ru(bipy)(CO)(2)Cl-2] in aqueous HX and HX-HNO3 solutions (X=F,Br or I; bipy=2,2'-bipyridine) [J].
Haukka, M ;
Ahlgren, M ;
Pakkanen, TA .
JOURNAL OF THE CHEMICAL SOCIETY-DALTON TRANSACTIONS, 1996, (09) :1927-1933