Design of clinically useful macromolecular iron chelators

Abstract

Objectives In recent years, macromolecular iron chelators have received increasing attention as human therapeutic agents. The objectives of this article are: one, to discuss the factors which should be considered when designing iron binding macromolecules as human therapeutic agents, and two, to report recent achievements in the design and synthesis of appropriate macromolecular chelators that have resulted in the production of a number of agents with therapeutic potential. Key findings Macromolecular drugs exhibit unique pharmaceutical properties that are fundamentally different from their traditional small-molecule counterparts. By virtue of their high-molecular-weight characteristics, many are confined to extracellular compartments, for instance, the serum and the gastrointestinal tract. In addition, they have potential for topical administration. Consequently, these macromolecular drugs are free from many of the toxic effects that are associated with their low-molecular-weight analogues. Summary The design and synthesis of macromolecular iron chelators provides a novel aspect to chelation therapy. 3-Hydroxypyridin-4-one hexadentate-based macromolecular chelators have considerable potential for the development of new treatments for iron overload and for topical treatment of infection.

Polymer antidotes for toxin sequestration

“…The utility of this ligand was previously discovered by Hider and colleagues while exploring various dendritic architectures for iron sequestration [115]. This work and other macromolecular iron chelators were reviewed extensively by Hinder [116] and also Dhal et al [117]. The culmination of these investigations reveals that like biological toxins, multivalent interactions with metals may also be utilized to increase the decontamination potential of the materials.…”

Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

“…[83,84] Da es bei extrazellulärw irkenden antimikrobiellen Metallchelatoren keine Grçßenbeschränkungen gibt, ist die hçhere thermodynamische und kinetische eine hçhere Affinitätf ürF e 3+ und eine hçhere antimikrobielle Aktivitäta ls Diethylentriaminpentaessigsäure (DTPA, 51) [84,85] (Abbildung 15), und ihre Fe 3+ -Komplexe werden von E. coli oder S. aureus nicht aufgenommen. [83,84] Da es bei extrazellulärw irkenden antimikrobiellen Metallchelatoren keine Grçßenbeschränkungen gibt, ist die hçhere thermodynamische und kinetische eine hçhere Affinitätf ürF e 3+ und eine hçhere antimikrobielle Aktivitäta ls Diethylentriaminpentaessigsäure (DTPA, 51) [84,85] (Abbildung 15), und ihre Fe 3+ -Komplexe werden von E. coli oder S. aureus nicht aufgenommen.…”

“…[ [81,82] Auch die Hydroxypyridinone (HOPOs) 44-46 erfüllen diese Anforderung und haben daher das Interesse als alternative eisenbindende Einheiten geweckt (Abbildung 13). [81,[83][84][85][86][87][88] In ihrer deprotonierten Form stellen diese Liganden benachbarte Sauerstoffdonoren bereit, die fünfgliedrige Chelatringe bilden kçnnen und thermodynamisch mit den chelatisierenden Einheiten der natürlichen Siderophore konkurrieren kçnnen, z. B. Catecholat-, Hydroxamat-und Hydroxycarboxylat-Gruppen.…”

Polymeric drugs: Advances in the development of pharmacologically active polymers

“…Several research groups have attempted to attach DFO to various biocompatible polymers, including dextran, hydroxyethyl-starch [68], PEG [69] and hyperbranched polyglycerol [70] to prolong the blood circulation time. Zhou et al have developed a series of brushed or dendritic polymeric iron sequestrants terminated with hexadentate ligands formed from hydroxypyridinone, hydroxypyranone, and catechol and showed high selectivity for iron(III) [71,72]. Later studies revealed that polymeric sequestrants based on the hydroxypyridinone hexadentate (CP254) provide the optimum coordination interactions with iron (III) to form highly stable complexes [72,73].…”

“…Zhou et al have developed a series of brushed or dendritic polymeric iron sequestrants terminated with hexadentate ligands formed from hydroxypyridinone, hydroxypyranone, and catechol and showed high selectivity for iron(III) [71,72]. Later studies revealed that polymeric sequestrants based on the hydroxypyridinone hexadentate (CP254) provide the optimum coordination interactions with iron (III) to form highly stable complexes [72,73]. Similar approaches using polymers modified with various iron-chelating motifs were reported and shown in vivo iron-binding capability in rats when given orally [74,75].…”