Hydrazone chelators for the treatment of iron overload disorders: iron coordination chemistry and biological activity

Bernhardt, Paul V.; Chin, Piao; Sharpe, Philip C.; Richardson, Des R.

doi:10.1039/b704102k

Cited by 98 publications

(93 citation statements)

References 62 publications

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“…6B). These results indicate that both these ligands are inefficient at permeating fibroblasts and releasing 59 Fe, probably because of their higher hydrophilicity compared with other PCIH analogs (Bernhardt et al, 2007). This low iron chelation efficacy could explain their lack of activity at preventing the cytotoxic effects of H 2 O 2 (Fig.…”

Section: Pcth Rescues H 2 O 2 -Mediated Cytotoxicity In Fibroblasts Fmentioning

confidence: 81%

“…As shown in previous studies in neoplastic cells (Becker and Richardson, 1999), the relatively hydrophilic PCIH analogs PCHH and PCAH (Bernhardt et al, 2007) were ineffective at mobilizing 59 Fe, with there being no significant (p Ͼ 0.05) difference compared with the control medium alone (Fig. 6B).…”

Section: Pcth Rescues H 2 O 2 -Mediated Cytotoxicity In Fibroblasts Fmentioning

confidence: 91%

“…DFO was purchased from Novartis (Basel, Switzerland). The PCIH analogs and PIH were prepared using standard procedures (Bernhardt et al, 2007). Deferiprone was a gift from Prof. Roger Dean (Heart Research Institute, Sydney, Australia).…”

Section: Methodsmentioning

confidence: 99%

“…1) analogs (Becker and Richardson, 1999). These chelators are tridentate (Bernhardt et al, 2007) and were derived from the highly effective pyridoxal isonicotinoyl hydrazone (PIH; Fig. 1) ligand (Ponka et al, 1979).…”

mentioning

confidence: 99%

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Protection against Hydrogen Peroxide-Mediated Cytotoxicity in Friedreich's Ataxia Fibroblasts Using Novel Iron Chelators of the 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone Class

2008

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Iron-loading diseases remain an important problem because of the toxicity of iron-catalyzed redox reactions. Iron loading occurs in the mitochondria of Friedreich's ataxia (FA) patients and may play a role in its pathogenesis. This suggests that iron chelation therapy could be useful. We developed previously the lipophilic iron chelators known as the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) ligands and identified 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH) as the most promising analog. Hence, this study assessed the efficacy of PCTH and other PCIH analogs compared with various chelators, including deferiprone and desferrioxamine (DFO). Ageand sex-matched control and FA fibroblasts were preincubated with iron chelators and subsequently challenged with 50 M H 2 O 2 for up to 24 h. The current study demonstrates an interesting structure-activity relationship among the closely related PCIH series of ligands, with only PCTH being highly effective at preventing H 2 O 2 -induced cytotoxicity. PCTH increased FA fibroblast cell viability by up to 70%, whereas DFO rescued viability by 1 to 5% only. Hence, PCTH, which was well tolerated by cells was far more effective than DFO at preventing oxidative stress. It is noteworthy that kinetic studies demonstrated PCTH to rapidly penetrate cells to induce 59 Fe efflux, whereas DFO, PCIH, 2-pyridylcarboxaldehyde benzoyl hydrazone, and 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone were far slower, indicating it is the rate of chelator permeation that is crucial for protection against H 2 O 2 . In addition, PCTH was found to be as effective as or more effective than conventional radical scavengers or the antioxidant idebenone (which has undergone clinical trials) at protecting cells against H 2 O 2 -mediated cytotoxicity. These findings further indicate the potential of PCTH for treatment of iron overload.

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Section: Pcth Rescues H 2 O 2 -Mediated Cytotoxicity In Fibroblasts Fmentioning

confidence: 81%

Section: Pcth Rescues H 2 O 2 -Mediated Cytotoxicity In Fibroblasts Fmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Protection against Hydrogen Peroxide-Mediated Cytotoxicity in Friedreich's Ataxia Fibroblasts Using Novel Iron Chelators of the 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone Class

2008

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“…As a peculiar Schiff-base, acylhydrazone have received great attention for its strong p-π conjugated system, various coordination forms, strong coordination abilities, good biological activity, [1][2][3][4][5] catalytic activity 6 and fluorescence property 7,8 in recent years. The strong conjugated system and high intramolecular electron transfer efficiency of carbazole make it have potential application prospect in electroluminescence (EL) and photoluminescence (PL).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Luminescence Properties of Nine Novel Carbazolyl Diacylhydrazone Schiff-bases

Wu¹,

Wu²,

Guo³

et al. 2015

Croat. Chem. Acta

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Abstract. Nine novel carbazolyl diacylhydrazone Schiff-bases were synthesized by alkylation, F-C acylation and condensation reactions starting from carbazole and hydrazide. The title Schiff-bases were characterized by 1 H NMR, MS, IR and elemental analysis. The synthetic conditions were optimized, and the best yield of the title Schiff-bases was up to 92.3 %. The relationships between the luminescence properties and the structures of the title Schiff-bases were studied. The results showed that the introduction of the Naphthalene-2-yloxy could form great plane conjugate structure to improve their luminescence properties.

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Photo‐ and Thermoresponsive Supramolecular Assemblies: Reversible Photorelease of K⁺ Ions and Constitutional Dynamics

Vantomme¹,

Lehn²

2013

Angewandte Chemie

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Hydrazone chelators for the treatment of iron overload disorders: iron coordination chemistry and biological activity

Cited by 98 publications

References 62 publications

Protection against Hydrogen Peroxide-Mediated Cytotoxicity in Friedreich's Ataxia Fibroblasts Using Novel Iron Chelators of the 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone Class

Protection against Hydrogen Peroxide-Mediated Cytotoxicity in Friedreich's Ataxia Fibroblasts Using Novel Iron Chelators of the 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone Class

Synthesis and Luminescence Properties of Nine Novel Carbazolyl Diacylhydrazone Schiff-bases

Photo‐ and Thermoresponsive Supramolecular Assemblies: Reversible Photorelease of K⁺ Ions and Constitutional Dynamics

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Hydrazone chelators for the treatment of iron overload disorders: iron coordination chemistry and biological activity

Cited by 98 publications

References 62 publications

Protection against Hydrogen Peroxide-Mediated Cytotoxicity in Friedreich's Ataxia Fibroblasts Using Novel Iron Chelators of the 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone Class

Protection against Hydrogen Peroxide-Mediated Cytotoxicity in Friedreich's Ataxia Fibroblasts Using Novel Iron Chelators of the 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone Class

Synthesis and Luminescence Properties of Nine Novel Carbazolyl Diacylhydrazone Schiff-bases

Photo‐ and Thermoresponsive Supramolecular Assemblies: Reversible Photorelease of K+ Ions and Constitutional Dynamics

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Product

Resources

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Photo‐ and Thermoresponsive Supramolecular Assemblies: Reversible Photorelease of K⁺ Ions and Constitutional Dynamics