Ring-Opened Adducts of the Anticancer Drug Carboplatin with Sulfur Amino Acids

Barnham, Kevin J.; Djuran, Miloš I.; Murdoch, Piedad del Socorro; Ranford, John D.; Sadler, Peter J.

doi:10.1021/ic950973d

Cited by 171 publications

(134 citation statements)

References 27 publications

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“…Met-298 appears to be the most surfaceaccessible Met residue, and most likely accounts for the sharp singlet in the 1 H NMR spectrum of albumin, which was suppressed upon cisplatin binding. The 1 H chemical shift of the ammine trans to sulfur cross-peak for this macrochelate complex (4.50 ppm) is shifted significantly to higher frequency (ϳ0.3 ppm) than has been observed for ammine trans to a methionine sulfur ligand (81 Apart from Met-298, Met-87 and Met-446 may also be involved in the formation of monofunctional adducts with cisplatin since these appear to be exposed residues.…”

Section: Possible Albumin Binding Sites For Cisplatinmentioning

confidence: 63%

Cisplatin Binding Sites on Human Albumin

Ivanov¹,

Christodoulou²,

Parkinson³

et al. 1998

Journal of Biological Chemistry

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332

288

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Section: Possible Albumin Binding Sites For Cisplatinmentioning

confidence: 63%

Cisplatin Binding Sites on Human Albumin

Ivanov¹,

Christodoulou²,

Parkinson³

et al. 1998

Journal of Biological Chemistry

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332

288

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“…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 ring-opening reactions (7,8). Exploration of the factors that control the aqueous chemistry of organometallic complexes may therefore also allow the design of effective anticancer agents.…”

mentioning

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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“…7) It was concluded that the reaction with carboplatin proceeds via a direct substitution mechanism, since the reaction with chloride was too slow to account for an aqua or chloro complex as the reactive species. [7][8][9][10][11] Tobe and Kokhar 12) reported that change in the amine ligands have primary effect on antitumor properties of platinum(II)/palladium(II) [Pt(II)/Pd(II)] complexes. Recent kinetic work by van Eldik and his co-workers.…”

mentioning

confidence: 99%