Organometallic ruthenium anticancer complexes inhibit human glutathione-S-transferase π.
The organometallic ruthenium(II) anticancer complexes [(η(6)-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.
Beijing National Laboratory for Molecular Sciences, Beijing 100190, PR China; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, PR China.
Yu
Y
Lin
Yongdong
Y
Huang
Wei
W
Zheng
Fuyi
F
Wang
Abraha
A
Habtemariam
Qun
Q
Luo
Xianchan
X
Li
Kui
K
Wu
Peter J
PJ
Sadler
Shaoxiang
S
Xiong
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000378:metabolism; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012428:Ruthenium / Q000737:chemistry*; D017975:Ruthenium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D007189:Indans; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C001723:methindione; D012428:Ruthenium; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D003545:Cysteine
Anticancer; Enzyme inhibition; Glutathione-S-transferase; Mass spectrometry; Organometallic ruthenium complex