Prochelator strategies for site-selective activation of metal chelators

Oliveri, Valentina; Vecchio, Graziella

doi:10.1016/j.jinorgbio.2016.05.012

Cited by 30 publications

(22 citation statements)

References 70 publications

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“…As an additional property, the drug should be able to pass the blood-brain barrier [78]. The ability of a CA to pass this barrier can be improved by the prochelator strategy, which for PD and also for other pathologies has been extensively reviewed by Oliveri and Vecchio [86].…”

Section: Metal Chelation Therapy In Parkinson's Diseasementioning

confidence: 99%

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

Tosato

Marco

2019

Biomolecules

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The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson’s disease (PD) therapy in the year range 2014–2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compounds has been collected or, if not experimentally available, has been estimated from similar molecules. Stoichiometries and stability constants of the complexes have been reported; values of the cologarithm of the concentration of free metal ion at equilibrium (pM), and of the dissociation constant Kd (both computed at pH = 7.4 and at total metal and ligand concentrations of 10–6 and 10–5 mol/L, respectively), charge and stoichiometry of the most abundant metal–ligand complexes existing at physiological conditions, have been obtained. A rigorous definition of the reported amounts is given, the possible usefulness of this data is described, and the need to characterize the metal–ligand speciation of PD drugs is underlined.

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Section: Metal Chelation Therapy In Parkinson's Diseasementioning

confidence: 99%

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

Tosato

Marco

2019

Biomolecules

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“…Neurodegeneratived iseases, however,p ose ag reat challenge for the application of classical metal-chelating compounds since the metal chelator design strategy has to point towards selectivity rathert han creating compounds that indiscriminately chelate immense amountso f metal. [5,6] Amongst the mosti mportant metal-binding compounds, the class of 8-hydroxyquinolines( HQs) has been identified as the most effective at preventing proteotoxicity caused by misfolded proteins through am etal-dependentm echanism. [7,8] In our previous studies, we demonstrated that glycoconjugation of HQ improvedo rp rovided new properties to the conjugates.…”

Section: Introductionmentioning

confidence: 99%

Zinc Complexes of Cyclodextrin‐bearing 8‐Hydroxyquinoline Ligands: A Comparative Study

Oliveri

Pietropaolo

Sgarlata

et al. 2016

Chemistry An Asian Journal

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The mounting evidence supporting the role of metal ions in several diseases has turned metal-ion chelation therapy into a promising treatment strategy. The design of efficient metal-binding ligands requires in-depth knowledge of molecular structure and stability constants of the complexes formed. This paper presents an extensive overview on the stability of zinc(II) and copper(II) complexes of a series of cyclodextrin-8-hydroxyquinoline conjugates. In order to explain the differences observed in the stability constants between the metal complexes of the 6-functionalized and 3-functionalized cyclodextrin isomers, conformational analysis and DFT simulations were also performed. Molecular simulations allowed us to clarify the binding mode and to explain the differences in the stability constants of the metal complexes of these derivatives.

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“…As it stands, our best 8-HNT compounds maintain an ∼100-fold therapeutic window; clearly, work will be required to improve selectivity. In the search for strategies to treat metal overload diseases, there is growing interest in the development of “prochelators” ( 50 – 52 ), molecules that have little affinity for metal ions until they undergo activation in response to specific stimuli. Activation generally involves the removal of a protective moiety by stimuli such as enzyme activation, oxidative stress, or reducing environments.…”

Section: Discussionmentioning

confidence: 99%

Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals

Wall

Moniz

Thomas

et al. 2018

Antimicrob Agents Chemother

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The lack of information regarding the mechanisms of action (MoA) or specific molecular targets of phenotypically active compounds can prove a barrier to their development as chemotherapeutic agents. Here, we report the results of our orthogonal genetic, molecular, and biochemical studies to determine the MoA of a novel 7-substituted 8-hydroxy-1,6-naphthyridine (8-HNT) series that displays promising activity against Trypanosoma brucei and Leishmania donovani.

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Prochelator strategies for site-selective activation of metal chelators

Cited by 30 publications

References 70 publications

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

Zinc Complexes of Cyclodextrin‐bearing 8‐Hydroxyquinoline Ligands: A Comparative Study

Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals

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