Ring-opening reactions of the anticancer drug carboplatin: NMR characterization of cis-[Pt(NH3)2(CBDCA-O)(5'-GMP-N7)] in solution

Frey, Urban; Ranford, John D.; Sadler, Peter J.

doi:10.1021/ic00060a005

Cited by 211 publications

(171 citation statements)

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“…These studies bring to the conclusion that CBDCA is attached through one carboxylate oxygen while 5´-GMP is attached through N7 of the purine base. The same finding was obtained from an NMR investigation of the ring opening reaction of carboplatin with phosphate, chloride, and 5´-guanosine monophosphate (5´-GMP) in aqueous solution at 310 K using 1 H, 15 N and 31 P NMR spectroscopy (Frey et al, 1993). In each case a ring-opened species containing monodentate CBDCA was detected during reaction development.…”

Section: Ring-opening Of [Pd(dap)(cbdca)] and The Formation Of [Pd(dasupporting

confidence: 74%

Coordination Chemistry of Palladium(II) Ternary Complexes with Relevant Biomolecules

El‐Sherif¹

2012

Stoichiometry and Research - The Importance of Quantity in Biomedicine

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Section: Ring-opening Of [Pd(dap)(cbdca)] and The Formation Of [Pd(dasupporting

confidence: 74%

Coordination Chemistry of Palladium(II) Ternary Complexes with Relevant Biomolecules

El‐Sherif¹

2012

Stoichiometry and Research - The Importance of Quantity in Biomedicine

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“…However, the main cause of the observed difference between the drugs is likely to be the slower rate of the second-arm reaction for carboplatin compared with cisplatin (Knox et al, 1986). Slow loss of the cyclobutanedicarboxylato group from monofunctional adducts on DNA and guanosine monophosphate was shown by Knox et al (1986) and Frey et al (1993) respectively. The immunoreactivity to ICR4 of the ultimate reaction products of carboplatin with DNA was the same as the immunoreactivity of cisplatin adducts (Tilby et al, 1991;B Peng et al, unpublished data), although recent data indicate slight differences in the distribution of adduct types formed by the two drugs (FichtingerSchepman et al, 1995).…”

Section: Discussionmentioning

confidence: 91%

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

Peng

Tilby²,

English³

et al. 1997

Br J Cancer

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Summary Platinum (Pt)-DNA adducts were measured in peripheral blood leucocytes (PBLs) from 24 children with solid tumours after standard cisplatin and/or carboplatin treatment. The relationship between Pt-DNA adduct levels and pharmacokinetics of cisplatin and carboplatin was investigated. Adduct measurements were performed by competitive enzyme-linked immunosorbent assay (ELISA) and plasma unbound Pt concentrations were measured by atomic absorption spectrophotometry (AAS). There was considerable interindividual variation in Pt-DNA adduct level that was weakly correlated (r 2 = 0.32) with the area under the unbound drug concentration vs time curve (AUC) at 6 h after the start of cisplatin infusion, indicating that the variation in Pt-DNA adduct levels was primarily determined by factors other than AUC. No clear relationship between AUC and adduct levels was seen at 24 and 48 h after cisplatin or at 6, 24 or 48 h after carboplatin. Carboplatin produced lower levels of immunoreactive adducts than did cisplatin (1.3±0.6 nmol Pt g-1 DNA vs 3.2 ± 1.7 nmol Pt g-' DNA), despite a 20-fold higher unbound drug AUC for carboplatin (8.0 ± 3.5 mg ml-' min vs 0.4 ± 0.2 mg ml-' min). This study demonstrates that, after cisplatin and carboplatin treatment the drug-target interaction is determined by both pharmacokinetic and, predominantly, cellular factors. Intrinsic differences between the two complexes, primarily reactivity, probably explain the lower adduct levels observed after carboplatin treatment.Keywords: cisplatin; carboplatin; Pt-DNA adduct; pharmacokinetics; child cancer Cisplatin and carboplatin are widely used in the treatment of solid tumours in childhood (Pinkerton et al, 1986;Pearson et al, 1992;Doz and Pinkerton, 1994). The activity and toxicity of cisplatin and carboplatin depend upon both pharmacokinetic and pharmacodynamic factors. A number of clinical pharmacokineticpharmacodynamic relationships have been described for cisplatin (Campbell et al, 1983;Reece et al, 1987;Thomas et al, 1994) and carboplatin (Egorin et al, 1984;Newell et al, 1987Newell et al, , 1993Harland et al, 1991;Horwich et al, 1991;Sorensen et al, 1991;Jodrell et al, 1992), and interpatient variability in tumour response to and/or tolerance of platinum (Pt)-complex therapy may relate to plasma levels more closely than to dose. Therefore optimum treatment with Pt drugs may necessitate adjustment for interindividual pharmacokinetic differences. Renal function-based dosing formulae have been developed for carboplatin administration to children (Marina et al, 1993;Newell et al, 1993;Chatelut et al, 1996) because carboplatin is cleared primarily by glomerular filtration.Although pharmacokinetics is one determinant of the clinical efficacy of Pt complexes, intracellular factors are certain to play an additional role. Pt complexes exert their anti-tumour effect by reacting with DNA (Roberts and Thomson, 1979;Sherman and Lippard, 1987;Fichtinger-Schepman et al, 1995 (Poirier et al, 1982;Fichtinger-Schepman et al, 1985;Terheggen et al, 1988; Tilby...

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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.…”

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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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301

298

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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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Ring-opening reactions of the anticancer drug carboplatin: NMR characterization of cis-[Pt(NH3)2(CBDCA-O)(5'-GMP-N7)] in solution

Cited by 211 publications

References 2 publications

Coordination Chemistry of Palladium(II) Ternary Complexes with Relevant Biomolecules

Coordination Chemistry of Palladium(II) Ternary Complexes with Relevant Biomolecules

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

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

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