Pre-association of polynuclear platinum anticancer agents on a protein, human serum albumin. Implications for drug design

Montero, Eva I.; Benedetti, Brad T.; Mangrum, John B.; Oehlsen, Michael J.; Qu, Yun; Farrell, Nicholas

doi:10.1039/b708433c

Cited by 40 publications

(41 citation statements)

References 29 publications

(43 reference statements)

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“…5 Cytotoxicity and cellular accumulation have also been shown to be charge-dependent. 1,7 1,0,1/ t,t,t has undergone Phase I 8 and Phase II 9,10 clinical trials, the only Pt( II ) agent structurally distinct from cisplatin and its analogs to do so. The products of degradation in blood plasma can be replicated by reactions with sulfur-containing proteins such as glutathione.…”

Section: Introductionmentioning

confidence: 99%

Solution studies of dinuclear polyamine-linked platinum-based antitumour complexes

et al. 2011

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The aquation profiles of two novel dinuclear polyamine-linked, platinum-based antitumour complexes [{trans-PtCl(15NH3)2}2{μ-(15NH2(CH2)615NH2(CH2)615NH2)}]3+ (BBR3007, 1,1/t,t-6,6, 1) and [{trans-PtCl(15NH3)2}2{μ-(15NH2(CH2)615NH2(CH2)215NH2(CH2)615NH2)}]4+ (BBR3610, 1,1/t,t-6,2,6, 1′) have been probed using 2D [1H, 15N] HSQC NMR spectroscopy. Reported herein are the rate constants for the hydrolysis of 1 and 1′, as well as the acid dissociation constants of the coordinated aqua ligands in their aquated derivatives. The aquation and anation rate constants for the single step aquation model in 15 mM NaClO4 (pH 5.4) at 298 K are, for 1, k1 = 7.2 ± 0.1 ×10−5 s−1, k−1 = 0.096 ± 0.002 M−1 s−1 and, for 1′, k1 = 4.0 ± 0.2 × 10−5 s−1, k−1 = 1.4 ± 0.1 M−1 s−1. The effect of the linker backbone (Pt(tetra(m)mine vs. polyamine) was evaluated by comparison with previous data for the trinuclear complex [{trans-PtCl(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (1,0,1/t,t,tor BBR3464). The pK1 for 1,0,1/t,t,t(3.44) is closest to that of 1 (3.12), while the pronounced difference for 1′ (4.54), means that 1′ is the least aquated of the three complexes at equilibrium. pKa values of 5.92 were calculated for the aquated forms of both 1 and 1′, which are 0.3 pKunits higher than for either 1,0,1/t,t,t, or the dinuclear 1,1/t,t. The higher pKa values for both polyamine-linked compounds may be attributed to the formation of macrochelates between the central NH2 groups and the {PtN3O}coordination sphere of the aquated species.

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Section: Introductionmentioning

confidence: 99%

Solution studies of dinuclear polyamine-linked platinum-based antitumour complexes

et al. 2011

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“…[161] nESI-QToF-MS and HPLC-ICP-MS experiments concluded that oxaliplatin was forming adducts with transferrin as the intact parent molecule as well as its hydrolysed species, in a stoichiometry that was concentration-dependent, but with no information of the potential binding sites on the protein. [162] The trinuclear platinum complex BBR3464 has also been characterised for its interactions with purified HSA using multiple techniques including ESI-MS. [163] Thanks to the central platinum moiety, a pre- Ruthenium-based complexes have also been studied for their interaction with serum proteins using different MS techniques. Once more, the results described in the literature concerning the selectivity and the affinity of ruthenium-based metallodrugs with serum proteins are quite controversial.…”

Section: Interactions Of Metallodrugs With Serum and Serum Proteinsmentioning

confidence: 99%

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Wenzel

Casini

2017

Coordination Chemistry Reviews

107

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Metal-based compounds form a promising class of therapeutic agents, whose mechanisms of action still need to be elucidated, and that are in general prone to undergo extensive speciation in physiological environment. Thus, determination of the fate of the metal compounds in complex biological systems, contributing to their overall pharmacological and toxicological profiles, is important to develop more rationalised and targeted metal-based drugs. To these aims, a number of spectroscopic and biophysical methods, as well as analytical techniques, are nowadays extensively applied to study the reactivity of metal complexes with different biomolecules (e.g. nucleic acids, proteins, buffer components). Among the various techniques, molecular mass spectrometry (MS) has emerged in the last decade as a major tool to characterise the interactions of metallodrugs at a molecular level. In this review, we present an overview of the information available on the reactivity of various families of therapeutic metallodrugs (mainly anticancer compounds based on Pt, Ru, Au and As) with biomolecules studied by different MS techniques, including high-resolution ESI-, MALDI-and ion mobility-MS among others. Representative examples on the potential of the MS approach to study non-covalent interactions are also discussed. The review is organized to present results obtained on samples with different degrees of complexity, from the interactions of metal compounds with small model nucleophiles (amino acids and nucleobases), model peptides/oligonucleotides, target proteins/nucleic acids, to the analysis of serum, cell extracts and tissue samples. The latter requiring combination of proteomic methods with advanced MS techniques. Correlations between molecular reactivity of metallodrugs and biological activity are hard to establish, but differences in the reactivity of metallodrugs to biomolecules and their different adducts, as revealed by MS methods, may indicate differences in their modes of action. Overall, the knowledge offered by MS methods on metallodrugs speciation is invaluable to establish new rules and define new trends in the periodic table aimed at rationalizing the behavior of metal compounds in complex living systems. Keywordsmetal-based drugs; proteins; nucleic acids; mass spectrometry; metallomics. Corresponding Author Angela Casini Corresponding Author's InstitutionCardiff University To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. Order of Authors 1 Answers to Reviewers Reviewer 1 The authors have made some effort to answer suggestions and the manuscript is improved. Since it is a review, there is, strictly, no new information but nevertheless the compilation of data and references could be useful.Answer: no further comments. Liu et al." in place of "Lu et al." iv) Some symbols in the PDF file are not correctly displayed. Reviewer Answer:We have inserted all the minor modifications requested by this rev...

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“…We describe the crosslinked nanoparticles, and also procedures for testing the degree of nanoparticle stability. Finally, for protein-based nanoparticles, it is essential to ensure that the protein molecules retain their native configuration, in order to preserve their specific functions [for HSA, this is the binding and transport of small molecules (Fehske et al 1981;Frokjaer and Otzen 2005;Goldwasser and Feldman 1997;Gonzalez and Kannewurf 1998;Griffel and Kaufman 1992;Kragh-Hansen 1981;Montero et al 2007;Peters 1985;Putnam 1984;Rainey and Read 1994)], and to avoid the potentially dangerous effects of denaturation, such as triggering amyloid formation (Schnabel 2010;Goldschmidt et al 2010;Balbirnie et al 2001;Nelson et al 2005). …”

Section: Introductionmentioning

confidence: 99%

Albumin-based nanoparticles as magnetic resonance contrast agents: II. Physicochemical characterisation of purified and standardised nanoparticles

Abdelmoez

Thurner

Wallnöfer

et al. 2010

Histochem Cell Biol

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We are developing a nanoparticulate histochemical reagent designed for histochemistry in living animals (molecular imaging), which should finally be useful in clinical imaging applications. The iterative development procedure employed involves conceptual design of the reagent, synthesis and testing of the reagent, then redesign based on data from the testing; each cycle of testing and development generates a new generation of nanoparticles, and this report describes the synthesis and testing of the third generation. The nanoparticles are based on human serum albumin and the imaging modality selected is magnetic resonance imaging (MRI). Testing the second particle generation with newly introduced techniques revealed the presence of impurities in the final product, therefore we replaced dialysis with diafiltration. We introduced further testing methods including thin layer chromatography, arsenazo III as chromogenic assay for gadolinium, and several versions of polyacrylamide gel electrophoresis, for physicochemical characterisation of the nanoparticles and intermediate synthesis compounds. The high grade of chemical purity achieved by combined application of these methodologies allowed standardised particle sizes to be achieved (low dispersities), and accurate measurement of critical physicochemical parameters influencing particle size and imaging properties. Regression plots confirmed the high purity and standardisation. The good degree of quantitative physicochemical characterisation aided our understanding of the nanoparticles and allowed a conceptual model of them to be prepared. Toxicological screening demonstrated the extremely low toxicity of the particles. The high magnetic resonance relaxivities and enhanced mechanical stability of the particles make them an excellent platform for the further development of MRI molecular imaging.

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Pre-association of polynuclear platinum anticancer agents on a protein, human serum albumin. Implications for drug design

Cited by 40 publications

References 29 publications

Solution studies of dinuclear polyamine-linked platinum-based antitumour complexes

Solution studies of dinuclear polyamine-linked platinum-based antitumour complexes

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Albumin-based nanoparticles as magnetic resonance contrast agents: II. Physicochemical characterisation of purified and standardised nanoparticles

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