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Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase π
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Lin, Yu, Huang, Yongdong, Zheng, Wei, Wang, Fuyi, Habtemariam, Abraha, Luo, Qun, Li, Xianchan, Wu, Kui, Sadler, P. J. and Xiong, Shaoxiang (2013) Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase π. Journal of Inorganic Biochemistry, Volume 128 . pp. 77-84. doi:10.1016/j.jinorgbio.2013.07.029 ISSN 0162-0134.
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Official URL: http://dx.doi.org/10.1016/j.jinorgbio.2013.07.029
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 ± 1.1 μM, 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.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
Journal or Publication Title: | Journal of Inorganic Biochemistry | ||||
Publisher: | Elsevier Science Inc | ||||
ISSN: | 0162-0134 | ||||
Official Date: | November 2013 | ||||
Dates: |
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Volume: | Volume 128 | ||||
Page Range: | pp. 77-84 | ||||
DOI: | 10.1016/j.jinorgbio.2013.07.029 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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