Reactions of a Ruthenium(II) Arene Antitumor Complex with Cysteine and Methionine

Wang, Fuyi; Chen, Haimei; Parkinson, John A.; Murdoch, Piedad del Socorro; Sadler, Peter J.

doi:10.1021/ic025538f

Cited by 119 publications

(98 citation statements)

References 50 publications

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“…Our previous work has shown that the interaction of [( 6 -bip)Ru(en)Cl] ϩ (2) with amino acids (38,39), peptides (40), proteins (39), and DNA bases (15) involves aquation as the first step. The chloro complexes are relatively inert.…”

Section: Discussionmentioning

confidence: 99%

Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

Wang

Habtemariam

Geer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional ''piano-stool'' ruthenium(II) arene complexes of the type [( 6 -arene)Ru(ethylenediamine)(X)] n؉ . A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X ‫؍‬ halide [arene ‫؍‬ hexamethylbenzene (hmb)]} or moderately slowly [e.g., X ‫؍‬ azide, dichloropyridine (arene ‫؍‬ hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X ‫؍‬ py) are inactive. An intriguing exception is the X ‫؍‬ thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.anticancer ͉ bioorganometallic ͉ hydrolysis ͉ kinetics ͉ ruthenium complexes O rganometallic chemistry has evolved rapidly during the last 50 years, notably in areas related to catalysis and materials (1). Applications in biology and medicine are in their infancy, but the potential for exciting developments is clear (2). In the field of cancer chemotherapy, the cyclopentadienyl complex [Cp 2 TiCl 2 ] has been in clinical trials (3, 4), and a ferrocene derivative of Tamoxifen is a candidate for trials for breast cancer therapy (5). The successful design of second-and thirdgeneration platinum anticancer drugs, now widely used in the clinic, has demonstrated that detailed knowledge of the factors that control ligand substitution and redox reactions is very valuable in drug design. The chemical reactivity of the complexes can be chosen so as to balance the inertness required for the drug to reach its target site (e.g., DNA) and minimize attack on other sites (side effects) yet allow activation necessary for binding to the target. Thus, cis-[PtCl 2 (NH 3 ) 2 ], cisplatin, is relatively unreactive in high-chloride media (e.g., blood plasma) and is activated by hydrolysis near DNA in the nucleus (6). In contrast, carboplatin and oxaliplatin are relatively inert to hydrolysis, have a milder spectrum of side effects, and probably attack DNA by means of chelate ...

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Section: Discussionmentioning

confidence: 99%

Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

Wang

Habtemariam

Geer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

296

298

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“…In the ideal case, such ligands would avoid the formation of aqua complexes, and thus prevent the coordination of competing biological ligands in vivo. [22,23] Thioether ligands are ideal candidates because ruthenium(II) likes binding to their soft sulfur atom. [24,25] Secondly, unlike nitrogen-based ligands, thioethers are only weakly basic in water, which might make their ruthenium complexes less sensitive to pH changes.…”

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confidence: 99%

N‐Acetylmethionine and Biotin as Photocleavable Protective Groups for Ruthenium Polypyridyl Complexes

Goldbach

Rodriguez‐Garcia

Lenthe

et al. 2011

Chemistry A European J

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“…Interestingly, the hydrolysis involved the displacement of the en ligand instead of the thiolate ligand, affording the di-aqua adduct 9 (Scheme 3, Figure S5). Sulfur-containing ligands such as cysteine and methionine are known to exhibit high trans effects in Pd(II) 48 , Pt(II) 49 and Ru(II) 21 coordination chemistry, labilizing metal-N bonds in the trans position.…”

Section: Reactions Of Thiolato Adduct 7 With H 2 O 2 and Gshmentioning

confidence: 99%

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

et al. 2011

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The organometallic anticancer complex [(h 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 [(h 6 -cym)Ru(en)(S-RS)] + (7 + , R = (C 6 H 4 )CONH(C 6 H 5 )) and a triply-S-bridged thiolato complex [((h 6 -cym)Ru) 2 (m-S-RS) 3 ] + (8 + ), respectively. Coordination of Ru to the S atom in 7 allows formation of a strong H-bond (2.02 A ˚) 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 mM) may be attributed to coordination to its catalytic cysteine.

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Reactions of a Ruthenium(II) Arene Antitumor Complex with Cysteine and Methionine

Cited by 119 publications

References 50 publications

Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

N‐Acetylmethionine and Biotin as Photocleavable Protective Groups for Ruthenium Polypyridyl Complexes

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

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