Design of Iron chelators: Syntheses and iron (III) complexing abilities of tripodal tris-bidentate ligands

Abstract

The interest in synthetic siderophore mimics includes therapeutic applications (iron chelation therapy), the design of more effective agents to deliver Fe to plants and the development of new chemical tools in order to study iron metabolism and iron assimilation processes in living systems. The design of ligands needs a rational approach for the understanding of the metal ion complexing abilities. The octahedral arrangement of donor atoms is the most favourable geometry, allowing the maximum possible distance between their formal or partial negative charges. Hexadentate chelators, usually of the tris-bidentate type, can accommodate the metal coordination sphere and are well-suited to obtain high pFe values. The first part of this review is dedicated to selected synthetic routes, taking into account (i) the nature of the chelating subunits, connecting groups and spacers, (ii) the water-solubility and hydrophilic/lipophilic balance, (iii) the chirality and (iv) the possibility of grafting probes or vectors. In the second part, we discuss the role of the molecular design on complexing abilities (thermodynamics and kinetics). The bidentate 8-hydroxyquinoline moiety offers an alternative to the usual coordinating hydroxamic acids, catechols and/or alpha-hydroxycarboxylic acids groups encountered in natural siderophores. The promizing results obtained with the tris-hydroxyquinoline-based ligand O-TRENSOX are summarized. O-TRENSOX exhibits a high and selective affinity for Fe(III) complexation. Its efficiency in delivering Fe to plants, iron mobilization, cell protection, and antiproliferative effects has been evidenced. Other chelators derived from O-TRENSOX (mixed catechol/8-hydroxyquinoline ligands, lipophilic ligands) are also described. Some results question the relevance of partition coefficients to foresee the activity of iron chelators. The development of probes (fluorescent, radioactive, spin labelled) based on the O-TRENSOX backbone is in progress in order to get insights in the complicated iron metabolism processes.

Synthesis, siderophore activity and iron(III) chelation chemistry of a novel mono-hydroxamate, bis-catecholate siderophore mimic: Nα,-Nε-Bis[2,3-dihydroxybenzoyl]-l-lysyl-(γ-N-methyl-N-hydroxyamido)-l-glutamic acid

“…The observed spectral changes (small red shift in k max , slight decrease in molar absorptivity) and isosbestic points ( Fig. 5A and B) are consistent with spectral changes previously reported for catechol-to-salicylate iron chelation mode conversions [19,26,[39][40][41]. The third protonation (pK MH3L = 4.1; Fig.…”

“…The pyoverdins are somewhat unique among naturally occurring siderophores in that they possess a combination of binding groups including a catecholate and a hydroxamate at the chain terminus, and either an additional hydroxamate or a hydroxycarboxylic acid in the middle of the chain [22,23]. The synthesis and characterization of several heterotripodal tris-bidentate siderophore mimics containing (i) two catecholates and one 8-hydroxyquionoline, (ii) two 8-hydroxyquinolines and one catechol, (iii) two hydroxypyridinones and one catecholate, and (iv) two 8-hydroxypyridinones and one 2-hydroxyisophtalamide, have been reported [24][25][26]. Here we present the synthesis, iron coordination properties, and biological activity of a novel heterotripodal, mono-hydroxamate, bis-catecholate siderophore mimic, N a ,-N e -bis[2,3-dihydroxybenzoyl]-L-lysyl-(c-N-methyl-N-hydroxyamido)-L-glutamic acid (H 6 L, Fig.…”

Dual purpose secondary compounds: phytotoxin of Centaurea diffusa also facilitates nutrient uptake

“…Thus, the diffusion of lipophilic FeQ could explain the higher tissue Fe 2+ concentration of test species despite their reduced root reductase activity in our FeQ systems. O‐Trensox is a synthetic chelator with three para‐ sulfonated 8HQ subunits that make it more hydrophilic (Baret et al ., 1995; d’Hardemare et al ., 2006). It has been reported to aid the Fe nutrition of dicotyledonous species (through extracellular chelate splitting as in Fe‐EDDHA, Strategy‐I) but not of Z. mays (as it lacks root‐reductase activity, Strategy‐II; Caris et al ., 1995).…”

In-depth analyses of B cell signaling through tandem mass spectrometry of phosphopeptides enriched by PolyMAC

“…We reason that the primary difference in the types of phosphopeptides isolated comes from the inherent coordination variations between the two metals. It has been previously suggested that iron metal ions are typically bound in a heterocyclic chelation format [28, 29], while titanium is immobilized through bidentate bridging coordination [10, 30]. This has also been recently confirmed for the bioactive form of Ti(IV) [31].…”