Complex formation equilibria of ligands with metal ions of biomedical interest
Notice bibliographique
Résumé
In a healthy situation, the body is provided with homeostatic mechanisms and buffers to maintain physiological concentrations of free metal ions, thus preventing their abnormal decompartmentalization, release and trafficking. The main reasons for the anomalous accumulation of non-essential metal ions in the body are environmental exposure and administration of metallodrugs for therapy or diagnosis, which may cause competition for biometals, generation of oxidative stress and disregulation of several metal-enzyme systems. Inorganic medicinal chemistry has to deal with the introduction of metal ions in the body, but also with their removal or passivation through the use of chelators. In these terms, thermodynamics and kinetics of complex formation are very important for a correct understanding of the role of metal ions in human diseases. \nDuring my PhD work, some new ligands were synthesized and their complex formation equilibria with toxic, essential and other metal ions of biomedical interest were studied. \nIn particular, some derivatives of kojic acid have been synthesized and their protonation and chelating properties toward the target metal ions Fe3+ and Al3+, and the two essential Cu2+ and Zn2+ have been characterized. Furthermore, the complex formation equilibria of some drugs actually in clinical use with the essential metal ions Cu2+ and Zn2+ were studied to give evidence of their possible implications in copper chelation. Moreover, the tyrosinase inhibitory properties of the kojic derivative[1] (5-hydroxy-4-oxo-4H-pyran-2-yl)methyl3-({[(5-hydroxy-4-oxo-4H-pyran-2yl)methoxy]carbonyl} amino)propanoate and its complex formation equilibria with copper have been studied, since the inhibitory effect may result from the interaction with copper ions in the active center of the enzyme. \nThis thesis is divided in an Introduction, dedicated to a description of metals, to their chemistry and their overload or deficiency, to chelation therapy, to the characteristics of chelators for metal overload treatment and to the improvements induced on some pathological conditions in diabetic patients. Further attention is devoted to tyrosinase inhibition and radiopharmaceutical labelling. An Experimental part describes the synthesis of new chelators and the methods used for a complete characterization. In the section Results and Discussion the determination of protonation constants for all ligands, together with that of their complex formation constants with metals of interest like Fe3+, Al3+, Ga3+, Cu2+ and Zn2+, is presented, in order to evaluate their therapeutic application in metal overload diseases. Complex stability studies of two new ligands with lanthanum to be used in the treatment of bone disorders are also presented as a part of a collaboration during my three month period at the University of British Columbia, Vancouver-Canada. A brief section Conclusions summarizes the presented results.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».