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Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase π.

Authors :
Lin, Yu
Huang, Yongdong
Zheng, Wei
Wang, Fuyi
Habtemariam, Abraha
Luo, Qun
Li, Xianchan
Wu, Kui
Sadler, Peter J.
Xiong, Shaoxiang
Source :
Journal of Inorganic Biochemistry. Nov2013, Vol. 128, p77-84. 8p.
Publication Year :
2013

Abstract

The organometallic ruthenium(II) anticancer complexes [(η6-arene)Ru(en)Cl]+ (arene= p-cymene (1), biphenyl (2) or 9,10-dihydrophenanthrene (3); en=ethylenediamine), exhibit in vitro and in vivo anticancer activities. In the present work, we show that they inhibit human glutathione-S-transferase π (GSTπ) with IC50 values of 59.4±1.3, 63.2±0.4 and 37.2±1.1μM, respectively. Mass spectrometry revealed that complex 1 binds to the S-donors of Cys15, Cys48 within the G-site and Cys102 at the interface of the GSTπ dimer, while complex 2 binds to Cys48 and Met92 at the dimer interface and complex 3 to Cys15, Cys48 and Met92. Moreover, the binding of complex 1 to Cys15 and Cys102, complex 2 to Cys48 and complex 3 to Cys15 induces the irreversible oxidation of the coordinated thiolates to sulfenates. Molecular modeling studies indicate that the coordination of the {(arene)Ru(en)}2+ fragment to Cys48 blocks the hydrophilic G-site sterically, perhaps preventing substrate from proper positioning and accounting for the reduction in enzymatic activity of ruthenated GSTπ. The binding of the ruthenium arene complexes to Cys102 or Met92 disrupts the dimer interface which is an essential structural feature for the proper functioning of GSTπ, perhaps also contributing to the inhibition of GSTπ. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
01620134
Volume :
128
Database :
Academic Search Index
Journal :
Journal of Inorganic Biochemistry
Publication Type :
Academic Journal
Accession number :
92872911
Full Text :
https://doi.org/10.1016/j.jinorgbio.2013.07.029