Issue 43, 2011

Reactions of an organoruthenium anticancer complex with 2-mercaptobenzanilide—a model for the active-site cysteine of proteintyrosine phosphatase 1B

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.

Graphical abstract: Reactions of an organoruthenium anticancer complex with 2-mercaptobenzanilide—a model for the active-site cysteine of protein tyrosine phosphatase 1B

Supplementary files

Article information

Article type
Paper
Submitted
23 Jun 2011
Accepted
22 Aug 2011
First published
30 Sep 2011

Dalton Trans., 2011,40, 11519-11529

Reactions of an organoruthenium anticancer complex with 2-mercaptobenzanilide—a model for the active-site cysteine of protein tyrosine phosphatase 1B

Y. Han, Q. Luo, X. Hao, X. Li, F. Wang, W. Hu, K. Wu, S. Lü and P. J. Sadler, Dalton Trans., 2011, 40, 11519 DOI: 10.1039/C1DT11189B

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