Effects of C-4 Stereochemistry and C-4‘ Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogues

Bergeron, Raymond J.; Wiegand, Jan; McManis, James S.; McCosar, Bruce H.; Weimar, William R.; Brittenham, Gary M.; Smith, Richard E.

doi:10.1021/jm990058s

Cited by 57 publications

(174 citation statements)

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Section: Resultsmentioning

confidence: 99%

“…However, the kidneys of the 1-treated rodents displayed mild damage to the proximal tubules. 52 In the current study, ligand 3 was given under the same experimental conditions. All of the rats survived the exposure period.…”

Section: Toxicity Evaluation In Rodentsmentioning

confidence: 99%

“…Because of the mild renal toxicity noted when 1 was given at 384 µmol/kg/day for 10 days, 52 we took the added precaution of iron overloading the rats 54,55 prior to the 30-day exposure. Because there were no drug-related abnormalities noted with 2 in the 10-day study, these animals were not iron loaded.…”

Section: Toxicity Evaluation In Rodentsmentioning

confidence: 99%

“…All histopathologies were normal except for the kidneys of rats treated with 1, which showed mild nephrotoxicity. 52 In a second trial, iron-loaded rodents were given 119 µmol/kg po of 1 for 30 days and sacrificed.No drug-related abnormalities were noted. When unloaded rodents were given 63.3 µmol/kg po of 2, a dose which clears the same amount of iron in the primates as 119 µmol/kg of 1, for 30 days and sacrificed, all histopathologies were normal.…”

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Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

Bergeron

Wiegand²,

McManis³

et al. 2008

J. Med. Chem.

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A series of iron-clearing efficiencies (ICEs), ferrokinetics, and toxicity studies for (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (deferitrin, 1), (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (2) and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (3) are reported. The ICEs in rodents are shown to be dose-dependent and saturable for ligands 2 and 3 and superior to 1. Both polyether analogues in subcutaneous (sc) versus oral (po) administration in rodents and primates demonstrated excellent bioavailability. Finally, in a series of toxicity studies of ligands 1-3, the dosing regimen was shown to have a profound effect in animals treated with ligand 1. When ligand 1 was given at doses of 237 µmol/kg/day twice a day (b.i.d.), there was serious proximal tubule damage versus 474 µmol/kg/day once daily (s.i.d.). With 2 and 3, in iron-overloaded and/or non-iron-loaded rodents, kidney histopathologies remained normal.Although iron comprises 5% of the earth's crust, living systems have great difficulty in accessing and managing this vital micronutrient. The low solubility of Fe(III) hydroxide (K sp = 1 × 10 −39 ), 1 the predominant form of the metal in the biosphere, has led to the development of sophisticated iron storage and transport systems in nature. Microorganisms utilize low molecular weight, virtually ferric ion-specific ligands, siderophores 2-6 higher eukaryotes tend to employ proteins to transport and store iron (e.g., transferrin and ferritin, respectively). [7][8][9] Humans absorb and excrete only about 1 mg of the metal daily; there is no effective mechanism for the excretion of excess iron. 10 In humans, nontransferrin-bound plasma iron, a heterogeneous pool of the metal in the circulation, unmanaged iron, seems to be a principal source of iron-mediated organ damage. Introduction of excess iron into this closed system, whether derived from transfused red blood cells [11][12][13] or from increased absorption of dietary iron, 14,15 leads to a build up of the metal in the liver, heart, pancreas, and elsewhere. Such iron accumulation eventually produces (i) liver disease that may progress to cirrhosis, [16][17][18] (ii) diabetes related both to iron-induced decreases in pancreatic β-cell secretion 19,20 and increases in hepatic insulin resistance, and (iii) heart disease, still the leading cause of death in thalassemia major [21][22][23] and related forms of transfusional iron overload.The toxicity associated with excess iron, whether a systemic or a focal problem, derives from its interaction with reactive oxygen species, for instance, endogenous hydrogen peroxide (H 2 O 2 ). [24][25][26][27] In the presence of Fe(II), H 2 O 2 is reduced to the hydroxyl radical (HO • ), a very reactive species, and HO − , a process known as the Fenton reaction. The Fe(III) liberated can NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript be reduced back to Fe(II) via ...

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Section: Resultsmentioning

confidence: 99%

Section: Toxicity Evaluation In Rodentsmentioning

confidence: 99%

Section: Toxicity Evaluation In Rodentsmentioning

confidence: 99%

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Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

Bergeron

Wiegand²,

McManis³

et al. 2008

J. Med. Chem.

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“…5) showed an interesting effect on iron clearing efficiency in the primate model. By retaining the same stereochemistry as DFT, the (S)-enantiomers of DMDFT and DADMDFT were more effective than their corresponding (R)-enantiomers in promoting iron clearance (Bergeron et al, , 1999a.…”

Section: A Siderophoresmentioning

confidence: 99%

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

2005

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Iron Chelators and Therapeutic Uses

Bergeron

McManis

Weimar

et al. 2003

Burger's Medicinal Chemistry and Drug Discovery

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Iron is an essential cofactor in a variety of biological redox reactions; life without this metal is virtually unknown. Because of its exceptionally poor solubility in the biosphere, bacteria produce relatively low molecular weight, virtually iron(III)‐specific, ligands, siderophores, for the purpose of acquiring this transition metal. On the other hand, higher eukaryotes generate proteins to acquire and store iron. In humans, the process of iron absorption and processing is very tightly controlled. However, the lack of an efficient means of elimination can, under certain conditions, result in iron overload, which can elicit oxidative tissue damage through the Fenton reaction. Accordingly, chelating agents have been tested over the last several decades for the purpose of rendering excess iron excretable. The currently accepted therapy for global iron overload, as occurs after repeated blood transfusions, is a siderophore, desferrioxamine B (DFO), which is administered subcutaneously as its mesylate salt (Desferal). Two synthetic agents, diethylenetriamine pentaacetic acid (DTPA) and 1,2‐dimethyl‐3‐hydroxypyridin‐4‐one (Ferriprox, deferiprone, L1), have been used for the treatment of iron overload as well. Unfortunately, all three of these ligands have drawbacks. The kinetics and lack of oral bioavailability of DFO require that this compound be administered subcutaneously 12 h/day, up to 6 days/week, a regimen with which many patients find it difficult to comply. The lack of chelating specificity of DTPA restricts its use to those who cannot tolerate therapy with DFO; questions remain unanswered regarding the efficacy and toxicity profile of L1. The ongoing efforts to find a worthy successor to DFO include the use of a synthetic agent, N,N ′‐bis(2‐hydroxybenzyl)ethylenediamine‐ N,N ′‐diacetic acid (HBED), which, although it would require subcutaneous administration, is significantly more efficient than DFO. Another avenue is using siderophores (e.g., desferrithiocin, parabactin) as platforms from which to design either orally or parenterally active iron chelators. Because of the necessity of striking a balance between efficacy (i.e., sufficient iron chelation) and toxicity (i.e., excessive iron removal), drug development in the arena of iron chelation therapy presents unique challenges. However, the application of sensible drug design principles predicated on our understanding of iron metabolism, modern synthetic techniques, and the use of appropriate animal models should bring about improved therapeutic agents for the treatment of both global and focal iron overload in the years to come.

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Effects of C-4 Stereochemistry and C-4‘ Hydroxylation on the Iron Clearing Efficiency and Toxicity of Desferrithiocin Analogues

Cited by 57 publications

References 23 publications

Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

Iron Chelators and Therapeutic Uses

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