2007
DOI: 10.1002/chem.200700887
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On the Hydrolysis Mechanism of the Second-Generation Anticancer Drug Carboplatin

Abstract: The hydrolysis reaction mechanisms of carboplatin, a second-generation anticancer drug, have been explored by combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The decomposition of carboplatin in water is expected to take place through a biphasic mechanism with a ring-opening process followed by the loss of the malonato ligand. We have investigated this reaction in water and acid conditions and established that the number of protons present in the mal… Show more

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Cited by 113 publications
(79 citation statements)
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“…We utilised molecular modelling to identify which p-Bel to develop with a view to facilitating complexation to Pt while minimising any negative impact on HDAC inhibitory activity. We anticipated that the dual functioning Pt-p-Bel conjugate would hydrolyse in much the same way as carboplatin in cells [17,18] by releasing the p-Bel derivative to inhibit HDACs and the cytotoxic cis-diammine Pt moiety to bind DNA nucleobases.…”
Section: Introductionmentioning
confidence: 99%
“…We utilised molecular modelling to identify which p-Bel to develop with a view to facilitating complexation to Pt while minimising any negative impact on HDAC inhibitory activity. We anticipated that the dual functioning Pt-p-Bel conjugate would hydrolyse in much the same way as carboplatin in cells [17,18] by releasing the p-Bel derivative to inhibit HDACs and the cytotoxic cis-diammine Pt moiety to bind DNA nucleobases.…”
Section: Introductionmentioning
confidence: 99%
“…The cyclobutane-1,1-dicarboxylate ligand has been shown to hydrate more slowly than the chloride ligands in 1, as this process involves ring-opening, followed by the loss of the ligand [4]. Under physiologically relevant conditions of 150 mm free chloride, as in most extracellular fluids, Pt II complexes can pass the membrane as neutral prodrugs and then become activated at 2 -4 mm chloride concentration prevailing in the cytoplasm and the organelles.…”
mentioning
confidence: 97%
“…Carboplatin has been shown to undergo hydrolysis via a classical ring opening process followed by hydration and consequent displacement of cyclobutane-1,1-dicarboxylate, to give DNA binding adducts such as [Pt(NH 3 ) 2 (H 2 O) 2 ] 2+ . 21,22 We envisaged that our Pt-malSAHA conjugate should act in much the same way as carboplatin releasing the malSAHA derivative thus free to inhibit HDAC's and the resulting Pt moiety free to bind DNA nucleobases.…”
mentioning
confidence: 99%