title: Reactions of an organoruthenium anticancer complex with 2-mercaptobenzanilide--a model for the active-site cysteine of protein tyrosine phosphatase 1B.
abstract: The organometallic anticancer complex [(η(6)-p-cymene)Ru(en)Cl]PF(6) (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 [(η(6)-cym)Ru(en)(S-RS)](+) (7(+), R = (C(6)H(4))CONH(C(6)H(5))) and a triply-S-bridged thiolato complex [((η(6)-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 H(2)O(2) and/or GSH were then investigated, demonstrating that coordination to Ru largely retards both the oxidation (deactivation) of the thiol in compound 2 by H(2)O(2) and the subsequent reduction (reactivation) of the sulfenyl-amide by GSH, implying that the inhibition of complex 1 on PTP1B (IC(50) of 19 μM) may be attributed to coordination to its catalytic cysteine.
authors.affiliation: CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, PR China.
authors.forename: Yumiao
authors.initials: Y
authors.lastname: Han
authors.forename: Qun
authors.initials: Q
authors.lastname: Luo
authors.forename: Xiang
authors.initials: X
authors.lastname: Hao
authors.forename: Xianchan
authors.initials: X
authors.lastname: Li
authors.forename: Fuyi
authors.initials: F
authors.lastname: Wang
authors.forename: Wenbing
authors.initials: W
authors.lastname: Hu
authors.forename: Kui
authors.initials: K
authors.lastname: Wu
authors.forename: Shuang
authors.initials: S
authors.lastname: Lü
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000813:Anilides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D013438:Sulfhydryl Compounds; D012428:Ruthenium; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D003545:Cysteine