Desferrithiocin Analogues and Nephrotoxicity

Bergeron, Raymond J.; Wiegand, Jan; McManis, James S.; Bharti, Neelam; Singh, Shailendra P.

doi:10.1021/jm8003398

Cited by 14 publications

(19 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The remaining rodents were euthanized 24 h post dosing due to their rapidly deteriorating condition. We had seen this same scenario with ( S )-2-(4-butoxy-2-hydroxyphenyl)-4,5-dihydro-4-thiazolecarboxylic acid, the 4'-butoxy analogue of 2 (log P app = 1.02), with deaths occurring within 24 h [76]. Nonetheless, 10 was a very active decorporation agent.…”

Section: Resultsmentioning

confidence: 87%

“…This ligand was very lipophilic (log P app = 0.95), had an ICE of 15.8 ± 3.7% in the rats, and was very toxic. We had seen this scenario before with a 4'-butoxy analogue of 2 (log P app = 1.02), with deaths occurring within 24 h [76]. Nevertheless, this ligand did serve to identify the upper boundary of the lipophilicity/toxicity relationship for this structural family.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolically programmed iron chelators

Bergeron

Bharti

McManis

et al. 2015

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Extensive structure activity relationship (SAR) studies focused on the desferrithiocin [DFT, (S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid] pharmacophore have led to three different DFT analogues being evaluated clinically for the treatment of iron overload diseases, e.g., thalassemia. The SAR work revealed that the lipophilicity of a ligand, as determined by its partition between octanol and water, log Papp, could have a profound effect on the drug’s iron clearing efficiency (ICE), organ distribution, and toxicity profile. While within a given structural family the more lipophilic a chelator the better the ICE, unfortunately, the more lipophilic ligands are often more toxic. Thus, a balance between lipophilicity, ICE, and toxicity must be achieved. In the current study, we introduce the concept of “metabolically programmed” iron chelators, i.e., highly lipophilic, orally absorbable, effective deferration agents which, once absorbed, are quickly converted to their nontoxic, hydrophilic counterparts.

show abstract

Section: Resultsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Metabolically programmed iron chelators

Bergeron

Bharti

McManis

et al. 2015

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…This led to the discovery that the lipophilicity (partition between octanol and water, expressed as the log of the fraction in the octanol layer, log P app ) 50 of the DADFT analogues could have a profound effect on the ligand's iron-clearing efficiency (ICE), organ distribution, and toxicity profile. 38,51,52 …”

Section: Resultsmentioning

confidence: 99%

Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron-Clearing and Toxicity Profiles

et al. 2012

Self Cite

View full text Add to dashboard Cite

Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. Iron clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron clearing properties.

show abstract

“…The link between the lipophilicity of the desferrithiocin analogues and Fe clearing efficiency has been investigated using two series of ligands of either 4' or 5' substituted versions of the parent compound and one 3' substituted example [111]. Lipophilicity was varied by changing the alkyl chain, giving logP values that varied from -1.22 to 2.05.…”

Section: Deferitrin and Desferrithiocinmentioning

confidence: 99%

Synthetic and Natural Products as Iron Chelators

Sharpe

Richardson²,

Kalinowski³

et al. 2011

CTMC

View full text Add to dashboard Cite

An evaluation of existing and proposed Fe chelators, both synthetic and natural products, for the treatment of Fe-overload disease must address a number of issues. There are fundamental parameters that determine the efficacy of a drug: absorption, distribution, metabolism, clearance and toxicity. However, the administration of chelator for Fe overload aims to generate Fe complexes in vivo that are able to be excreted. Hence, the chemical and pharmacological properties of the complexes formed are equally important as the chelators themselves. The redox properties of the Fe complexes formed is particularly relevant to their toxicity. If both Fe(II) and Fe(III) oxidation states of the complexes are biologically accessible, then there is potential for the auto-catalytic production of deleterious free radicals, by Fenton-type chemistry. In addition, since the burden of Fe overload disease falls predominantly on some of the poorest economies, the cost of a drug must be considered, as well as the mode of delivery. There are also possible issues with the use of naturally occurring ligands, which may form Fe complexes capable of being utilised by opportunistic bacteria. This review will concentrate on recent developments in our chemical understanding of existing chelators approved or proposed for use and will also consider some of the candidates from natural sources that have been recently proposed.

show abstract

Desferrithiocin Analogues and Nephrotoxicity

Cited by 14 publications

References 63 publications

Metabolically programmed iron chelators

Metabolically programmed iron chelators

Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron-Clearing and Toxicity Profiles

Synthetic and Natural Products as Iron Chelators

Contact Info

Product

Resources

About