A new tripodal tris(hydroxypyridinone) bifunctional chelator for gallium allows easy production of (68)Ga-labelled proteins rapidly under mild conditions in high yields at exceptionally high specific activity and low concentration.

A range of iron binding dendrimers terminated with hexadentate ligands formed from hydroxypyridinone, hydroxypyranone, and catechol moieties have been synthesized in order to investigate their potential as clinically useful iron(III)-selective chelators capable of removing dietary iron from the gastrointestinal tract and preventing the development of iron overload typical of haemochromatosis and thalassaemia intermedia. The iron chelating abilities of these molecules have been characterized by MALDI-TOF mass spectrometry and UV spectrometry. Hydroxypyridinone-terminated dendrimers were found to possess a high affinity and selectivity for iron(III). A hydroxypyridinone-based dendrimer was demonstrated to be highly efficient at reducing the absorption of iron(III) in rat intestine. This family of dendrimers may find an application in the treatment of iron overload.

Iron is essential for the proper functioning of all living cells, however it is toxic when present in excess. Thus, using iron chelators as therapeutic agents, namely chelation therapy, has received increasing attention. The objective of this review is to discuss the factors which should be considered when designing clinically useful iron chelators, to present the application of iron chelators in the treatment of iron overload associated with β-thalassaemia major and sickle cell anaemia, and to highlight the potential applications in the treatment of neurodegenerative disorders and microbial infection. This article reviews recent knowledge centred on these themes and indicates the growing importance of the concept of iron chelation in medicine.

The first successful therapeutic iron chelator was desferrioxamine which was introduced in the late 1960's by Ciba (now Novartis). Desferrioxamine has been an extremely successful compound having received the MMW "Pharmaceutical of the year" award for 1991. It is a life saving and a life - prolonging drug which improves the quality of life. However it is not orally active and its administration is both uncomfortable and expensive. Over the past twenty years there has been a growing interest in the orally active iron chelators, deferiprone and exjade, both having been extensively studied. The ability of these compounds to mobilize iron from the heart and endocrine tissue has presented the clinician with some advantages over desferrioxamine. Other orally active iron chelators are currently under development and one, FBS0701 is in clinical trial. The critical features necessary for the design of therapeutically useful iron chelators is presented in this review, together with recent studies devoted to the design of such chelators. This newly emerging range of iron chelators will enable clinicians to apply iron chelation methodology to other disease states and to begin to design personalised chelation regimes.

2 Highlights The degradation conditions of polysaccharide from S. fusiforme has been optimized. The antioxidant activity of the degraded polysaccharides was greatly improved. The degraded polysaccharides possess superior anti-tyrosinase activity.Abstract: An efficient method for the degradation of polysaccharides isolated from Sargassum fusiforme (PSF) was developed by using ascorbic acid in combination with H2O2. The degradation conditions were optimized using a Box-Behnken response surface design (BBRS). The optimum conditions were established as: concentration of ascorbic acid (VC) and H2O2 17.26 mM, degradation temperature 51 o C and degradation time 1.6 h. The DPPH radical scavenging rate of the degraded polysaccharides from S. fusiforme (DPSF) obtained under the optimal conditions was determined to be 75.22±0.02%, which was well matched with the value (75.21%) predicted by the BBRS model. In vitro antioxidant activity of the polysaccharides was evaluated by determining their radical (hydroxyl radical, superoxide anion radical and DPPH radical) scavenging abilities, and ferric iron reducing power. The inhibitory activity on tyrosinase of DPSF was also evaluated. The results indicate that the degraded polysaccharide has superior antioxidant activity and anti-tyrosinase effect to those of the original polysaccharide.

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We report the synthesis and characterization of a fluorescent iron chelator (4), shown to be effective in inhibiting the growth of Mycobacterium avium in macrophages, together with the synthesis and characterization of two unsuccessful analogues selected to facilitate identification of the molecular properties responsible for the antimicrobial activity. Partition of the chelators in liposomes was investigated and the compounds were assessed with respect to uptake by macrophages, responsiveness to iron overload/iron deprivation and intracellular distribution by flow cytometry and confocal microscopy. The synthesis of the hexadentate chelators is based on a tetrahedral structure to which three bidentate 3-hydroxy-4-pyridinone chelating units are linked via amide bonds. The structure is synthetically versatile, allowing further addition of functional groups such as fluorophores. Here, we analyse the non-functionalized hexadentate unit (3) and the corresponding rhodamine B (4) and fluorescein (5) labelled chelators. The iron(III) stability constant was determined for 3 and the values log beta = 34.4 and pFe(3+) = 29.8 indicate an affinity for iron of the same order of magnitude as that of mycobacteria siderophores. Fluorescence properties in the presence of liposomes show that 4 strongly interacts with the lipid phase, whereas 5 does not. Such different behaviour may explain their distinct intracellular localization as revealed by confocal microscopy. The flow cytometry and confocal microscopy studies indicate that 4 is readily engulfed by macrophages and targeted to cytosol and vesicles of the endolysosomal continuum, whereas 5 is differentially distributed and only partially colocalizes with 4 after prolonged incubation. Differential distribution of the compounds is likely to account for their different efficacy against mycobacteria.

Hydroxypyridinones (HOPOs) form outstanding building blocks for the development of a variety of agents in the field of metal chelation. The pyridinone ring is easily synthesized and readily converted into tetradentate, hexadentate, and octadentate chelators. There is considerable potential for the control of the stereochemistry of the resulting metal complex and hence the properties of these multidentate molecules. Their ability to rapidly bind hard metals in aqueous media has facilitated the development of efficient applications in both biological and medical contexts. In this Review, an in-depth analysis of the synthetic methodologies for HOPO-based ligands is presented, as well as the many aspects to achieve optimal biological activity. Recent advances and current challenges for the future application of HOPO structures are outlined. The present flourishing development of drug candidates and diagnostic agents based on this chemical scaffold opens access to many new applications in analytical, environmental, and clinical science.