Han, Yumiao, Luo, Qun, Hao, Xiang, Li, Xianchan, Wang, Fuyi, Hu, Wenbing, Wu, Kui, Lü, Shuang and Sadler, P. J.. (2011) Reactions of an organoruthenium anticancer complex with 2-mercaptobenzanilide — a model for the active-site cysteine of protein tyrosine phosphatase 1B. Dalton Transactions, Vol.40 (No.43). pp. 11519-11529. ISSN 1477-9226

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Abstract

The organometallic anticancer complex [(η6-p-cymene)Ru(en)Cl]PF6 (1, en = ethylenediamine) readily reacts with thiols and forms stable sulfenate/sulfinate adducts which may be important for its biological activity. Protein tyrosine phosphatase 1B (PTP1B), a therapeutic target, contains a catalytic cysteinyl thiol and is involved in the regulation of insulin signaling and the balance of protein tyrosine kinase activity. On oxidation, the catalytic Cys215 can form an unusual sulfenyl-amide intermediate which can subsequently be reduced by glutathione. Here we study reactions of 1 with 2-mercaptobenzanilide, 2, a recognized model for the active site of PTP1B. We have characterized crystallographically compound 2 and its oxidized sulfenyl-amide derivative 2-phenyl-1,2-benzisothiazol-3(2H)-one (4), which shows a close structural similarity to the sulfenyl-amide in oxidized PTP1B. At pH 7.4 and 5.3, 1 reacted with 2, affording a mono-ruthenium thiolato complex [(η6-cym)Ru(en)(S-RS)]+ (7+, R = (C6H4)CONH(C6H5)) and a triply-S-bridged thiolato complex [((η6-cym)Ru)2(μ-S-RS)3]+ (8+), respectively. Coordination of Ru to the S atom in 7 allows formation of a strong H-bond (2.02 Å) between the en-NH and the carbonyl oxygen. To assess the possible effect of ruthenium coordination on the redox regulation of PTP1B, reactions of these thiolato products with H2O2 and/or GSH were then investigated, demonstrating that coordination to Ru largely retards both the oxidation (deactivation) of the thiol in compound 2 by H2O2 and the subsequent reduction (reactivation) of the sulfenyl-amide by GSH, implying that the inhibition of complex 1 on PTP1B (IC50 of 19 μM) may be attributed to coordination to its catalytic cysteine.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Organoruthenium compounds -- Therapeutic use, Organometallic compounds -- Therapeutic use, Antineoplastic agents, Biosynthesis, Catalysis
Journal or Publication Title:	Dalton Transactions
Publisher:	Royal Society of Chemistry
ISSN:	1477-9226
Date:	21 November 2011
Volume:	Vol.40
Number:	No.43
Page Range:	pp. 11519-11529
Identification Number:	10.1039/c1dt11189b
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Guo jia zi ran ke xue ji jin wei yuan hui (China) [National Natural Science Foundation of China] (NSFC), China. Guo jia ke xue ji shu bu [Ministry of Science and Technology of China], Zhongguo ke xue yuan [Chinese Academy of Sciences] (CAS), European Research Council (ERC)
Grant number:	90713020 (NSFC), 20975103 (NSFC), 21005081 (NSFC), 21020102039 (NSFC), 2007CB935601 (MOST), 2007CB935601 (MOST), 247450 (ERC)
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URI:	http://wrap.warwick.ac.uk/id/eprint/40368

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