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Synthesis and thermodynamic evaluation of mixed hexadentate linear iron chelators containing hydroxypyridinone and terephthalamide units.

ABSTRACT: A series of new linear iron chelators containing hydroxypyridinone and terephthalamide (TAMmeg) moieties have been prepared. All are hexadentate ligands composed of a systematically varied combination of methyl-3,2-hydroxypyridinone and 2,3-dihydroxyterephthalamide binding units; most are based on a spermidine scaffold, but one incorporates the bifunctional 2,3-dihydroxyterephthalamide unit as an integral part of the backbone. Protonation and ferric iron complex formation constants have been determined from solution thermodynamic studies, giving log beta(110) values of 25.7, 30.7, 36.3, 43.8, and 45.0, respectively. The ferric complexes display reversible reduction potentials from -276 to -1032 mV (measured relative to the normal hydrogen electrode) in alkaline solution. The incremental replacement of hydroxypyridinone units by terephthalamide binding groups progressively reduces the ligand acidity, markedly increases the iron-chelate stability, and improves the selectivity for the ferric ion over the ferrous ion. While the majority of iron chelators forming very stable ferric complexes are based on a tripodal backbone such as TREN, the ferric 5-LIO(TAMmeg)(2)(TAM) complex, despite its nontripodal scaffold, is one of the most stable iron complexes yet reported. Moreover, the high affinity for the ferric ion of the discussed linear ligands strongly correlates with their ability to remove iron in vivo.

SUBMITTER: Abergel RJ

PROVIDER: S-EPMC3685440 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Synthesis and thermodynamic evaluation of mixed hexadentate linear iron chelators containing hydroxypyridinone and terephthalamide units.

Abergel Rebecca J RJ Raymond Kenneth N KN

Inorganic chemistry 20060501 9

A series of new linear iron chelators containing hydroxypyridinone and terephthalamide (TAMmeg) moieties have been prepared. All are hexadentate ligands composed of a systematically varied combination of methyl-3,2-hydroxypyridinone and 2,3-dihydroxyterephthalamide binding units; most are based on a spermidine scaffold, but one incorporates the bifunctional 2,3-dihydroxyterephthalamide unit as an integral part of the backbone. Protonation and ferric iron complex formation constants have been det ...[more]

PMID: 16634594

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Project description:BackgroundStroke is the second leading cause of death and a major cause of morbidity worldwide. Retrospective clinical and animal studies have demonstrated neuroprotective effects of iron chelators in people with haemorrhagic or ischaemic stroke. This is the first update of the original Cochrane Review published in 2012.ObjectivesTo evaluate the effectiveness and safety of iron-chelating drugs in people with acute stroke.Search methodsWe searched the Cochrane Stroke Group Trials Register (2 September 2019), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2019, Issue 9; 2 September 2019), MEDLINE Ovid (2 September 2019), Embase Ovid (2 September 2019), and Science Citation Index (2 September 2019). We also searched ongoing trials registers.Selection criteriaWe included randomised controlled trials (RCTs) of iron chelators versus no iron chelators or placebo for the treatment of acute stroke, including subarachnoid haemorrhage.Data collection and analysisTwo review authors independently screened the search results. We obtained the full texts of potentially relevant studies and evaluated them for eligibility. We assessed risk of bias using the Cochrane 'Risk of bias' tool, and the certainty of evidence using the GRADE approach.Main resultsTwo RCTs (333 participants) were eligible for inclusion; both compared the iron-chelating agent deferoxamine against placebo. Both studies evaluated participants with spontaneous intracerebral haemorrhage. We assessed one study to have a low risk of bias; the other study had potential sources of bias. The limited and heterogeneous data did not allow for meta-analysis of the outcome parameters. The evidence suggests that administration of deferoxamine may result in little to no difference in deaths (8% in placebo vs 8% in deferoxamine at 180 days; 1 RCT, 291 participants; low-certainty evidence). These RCTs suggest that there may be little to no difference in good functional outcome (modified Rankin Scale score 0 to 2) between groups at 30, 90 and 180 days (placebo vs deferoxamine: 67% vs 57% at 30 days and 36% vs 45% at 180 days; 2 RCTs, 333 participants; low-certainty evidence). One RCT suggests that administration of deferoxamine may not increase the number of serious adverse events or deaths (placebo vs deferoxamine: 33% vs 27% at 180 days; risk ratio 0.81, 95 % confidence interval 0.57 to 1.16; 1 RCT, 291 participants; low-certainty evidence). No data were available on any deaths within the treatment period. Deferoxamine may result in little to no difference in the evolution of National Institute of Health Stroke Scale scores from baseline to 90 days (placebo vs deferoxamine: 13 to 4 vs 13 to 3; P = 0.37; 2 RCTs, 333 participants; low-certainty evidence). Deferoxamine may slightly reduce relative oedema surrounding intracerebral haemorrhage at 15 days (placebo vs deferoxamine: 1.91 vs 10.26; P = 0.042; 2 RCTs, 333 participants; low-certainty evidence). Neither study reported quality of life.Authors' conclusionsWe identified two eligible RCTs for assessment. We could not demonstrate any benefit for the use of iron chelators in spontaneous intracerebral haemorrhage. The added value of iron-chelating therapy in people with ischaemic stroke or subarachnoid haemorrhage remains unknown.

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Synthesis and thermodynamic evaluation of mixed hexadentate linear iron chelators containing hydroxypyridinone and terephthalamide units.

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Synthesis and thermodynamic evaluation of mixed hexadentate linear iron chelators containing hydroxypyridinone and terephthalamide units.

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