Study On Synthesis And Properties Of 3-Hydroxypyridin- 4-one Ligand-Containing Polymeric Iron Chelators

In recent years, macromolecular iron chelators have received increasing attention as human therapeutic agents. Polymeric chelators have been used for water treatment, pollution control, recovery of metals, active packaging and in analytical chemistry. Recently several iron binding polymer applications in the biomedical field have also been reported. As iron is an important element for all living processes, in principle targeting iron is a useful approach for the treatment of microbial infectious diseases. Macromolecular iron chelators also have a role in the treatment of both chronic and acute iron overload. Although most of the present-day iron-chelating therapeutics are designed as small molecules, a re-evaluation of the attributes of polymers has revealed a number of advantages associated with polymeric therapeutics that cannot be readily achieved with traditional small-molecule drugs. For example, when taken orally, the high-molecular-weight characteristics of polymers render them largely non-absorbed by the gastrointestinal tract. According to the current situation of treatment of thelassemia and iron overload, a series of 5-hydroxypyran-4-one derivatives, PEGylated 3-hydroxypyridin-4-ones (HPOs) and macromolecular iron chelators have been designed and synthesized. The final products were identified and characterized using 13C,1H NMR, and high resolution mass spectroscopy. The purity of the compounds were determined by HPLC method. In this dissertation, we focus on the synthesis, physico-chemical properties, antibacterial, iron-chelating activity, as well as the clinical application of the iron chelators and the iron-binding polymers. Specifically, the dissertation can be further categorized into the following four parts.1. Kojic acid can be condensed with amines via the Mannich reaction in good yield without protection of the phenolic group. Using this synthetic approach a series of 5-hydroxypyran-4-one derivatives have been prepared. All these possess a high affinity for iron(Ⅲ), a pFeⅢ value of 21.5 being associated with the hexadentate ligand which renders it a useful lead chelator for clinical application.2. A series of PEGylated 3-hydroxypyridin-4-ones have been designed and synthesized where PEGylated substituent was attached at 1-,2-,6-or both 2-and 6-position of the pyridine ring in order to improve the physicochemical properties of HPOs, as well as took advantage of the unique properties of PEGs, a non-toxic, non-immunogenic polymer approved by the US FDA for internal use. The physicochemical properties of this series of compounds have been characterized, together with their metabolic stability. The synthetic route in which PEG counterparts is introduced to a protected pyran ring via Williamson etherification reaction or directly adduction gave a polyethylene glycol containing precursor. The pKa values of the free ligands and the affinity constants of their iron complexes demonstrate that the presence of PEG dramatically alters the values’. Glucuronidation and oxidation studies of selected PEGylated 3-hydroxypyridin-4-ones demonstrate that some such pegylated compounds have clear advantage over deferiprone in that they are metabolized more slowly.3. The synthesis of a series of HPO bidentate ligands with different amines and PGMA with different molecular weight, as well as the post-polymerization modification by nucleophilic ring-opening reaction of the epoxy group is reported. For the first time, RAFT polymerization was employed to generate well-controlled polymeric HPO-based macromolecular chelators. These polymers, which contain one bidentate ligand in every structural unit are novel and have not been previously reported. The synthetic method was simple with high yield and low cost, thus the approach could be applied to synthesis of other types of functional materials. An investigation of the physicochemical characterization of the monomer bidentate ligand and the iron-chelating properties of this class of polymer has been undertaken.4. A series of prepolymers with high reactivity were synthesized and conjugated with amine-containing HPOs to generate a panel of HPO-containing materials with controlled structures and specific iron-binding functions, the synthetic method is simple with high yield and low cost, and thus the approach could be applied to the syntheses of other related types of functional materials.(1) We designed and synthesized a kind of azo-containing polymers, it could be served as a type of additive to polyurethane solution or emulsion, thus we could get a kind of colorful and azo functional polyurethane materials with a low small molecular dyes migration propensity. In this way, It could be overcome the deficiencies of limitation of the introduction of small molecule reactive dyes as reaction reagent, macromolecular dyes dibasic alcohol as reactants which required complicated multi-step synthesis, it is also has an effect on performance after introducing the such reactive dyes, and it is very inconvenient to use such materials. Moreover, the azo-containing polymers not only be applied in the field of polyurethane materials, but also be applied in the polyester, polyethylene, polyether, fiber, and other type of material.(2) Polyurethane prepolymers with end groups of isocyanate were prepared by chemical synthesis, and then use isocyanate groups react with compounds containing hydroxyl and double bond, such as hydroxyethyl methylacrylate, hydroxyethyl acrylate to get polymers with end groups of double bonds, and then use the double bonds react with glycidyl methacrylate through free radical reaction to synthesize a kind of epoxy modified cationic waterborne polyurethane emulsion with both ends of the block copolymer containing epoxy units, and the epoxy groups are stable at room temperature.(3) Epoxy modified cationic waterborne polyurethane emulsion with both ends of the block copolymer containing epoxy units could be applied to synthesis of other types of functional materials via the epoxy opening reaction with amine compounds.(4) a novel type of cationic waterborne polyurethane containing azo groups has been synthesized by incorporating the azo units of 2,20-(4-((4-ethylphenyl)diazenyl)phenylazane-diyl)diethanol (EDPD) into the polymer chains via copolymerization. This reaction route can provide a convenient and simple way to synthesize side-chain azo polymer dispersion. The acidity-structure and UV radiation-structure relation of the polymer has been studied and discussed in detail, as well as the effect of azo units on the thermal stability and hydrodynamic radius of polymer. Additionally, the polymer can be dispersed in aqueous solutions making it suitable for use especially when environment considerations have to be taken into account. Such properties are promising for applications in areas such as functional coatings, optical devices, chemosensors, organic LEDs, and laser active media.