Methoxylation of Desazadesferrithiocin Analogues:  Enhanced Iron Clearing Efficiency

Bergeron, Raymond J.; Wiegand, Jan; McManis, James S.; Bussenius, Joerg; Smith, Richard E.; Weimar, William R.

doi:10.1021/jm020412d

Cited by 36 publications

(101 citation statements)

References 56 publications

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“…1, eq. 2). The highly reactive OH ⅐ radical is able to induce cell death through initiating a series of chemical reactions with many significant biomolecules, resulting in DNA oxidation, mitochondrial damage, and the peroxidation of membrane lipids (Bergeron et al, 2003c;Barnham et al, 2004). In addition, excess free iron can also react with unsaturated lipids to produce alkoxyl and peroxyl radicals (Lieu et al, 2001).…”

Section: Redox Activity Of Ironmentioning

confidence: 99%

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

2005

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Section: Redox Activity Of Ironmentioning

confidence: 99%

“…In addition, the 4Ј-hydroxylated analog of the 5,5-dimethyl thiazoline DADMDFT derivative (Fig. 6) was found to have good iron chelation efficacy in the primate model (Bergeron et al, 2003c). The addition of a hydroxyl group at the 4-position of DADFT [4Ј-(OH)-DADFT; Fig.…”

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confidence: 99%

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

2005

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“…The parent drug 1 was given orally at 300 51 or 150 µmol/kg to bile duct-cannulated rodents. Iron clearance was minimal at each dose, 0.089 ± 0.068 mg Fe/kg and 0.061 ± 0.073 mg Fe/ kg, respectively (Table 1).…”

Section: Chelator-induced Iron Clearance and Iron Clearing Efficiencymentioning

confidence: 99%

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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“…39 The efficiency of 1 given po to iron-loaded primates was 16.8 ± 7.2%, 41 while the ICE of the 4′-(CH 3 O) analogue (2) given po was 24.4 ± 10.8%. 40 The corresponding polyether (3) given po performed very well in primates with an efficiency of 25.4 ± 7.4%. 39…”

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confidence: 94%

“…39,40,41 There also exists a second, albeit somewhat disturbing relationship: in all sets of ligands, the more lipophilic chelator is always the more toxic. 39 A previous investigation focused on the design of ligands that balance the lipophilicity/toxicity relationship while iron-clearing efficiency is maintained.…”

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Impact of the 3,6,9-Trioxadecyloxy Group on Desazadesferrithiocin Analogue Iron Clearance and Organ Distribution

et al. 2007

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The impact of introducing a 3,6,9-trioxadecyloxyl group at various positions of the desazadesferrithiocin (DADFT) aromatic ring on iron clearance and organ distribution is described. Three DADFT polyethers are evaluated: (S)-4,5-dihydro-2- [2-hydroxy-4-(3,6,9- trioxadecyloxy) phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4′-(HO)-DADFT-PE, 3], (S)-4,5-dihydro-2-[2-hydroxy-5-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-5′-(HO)-DADFT-PE, 6], and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3′-(HO)-DADFT-PE, 9]. The iron-clearing efficiency (ICE) in rodentsand primates is shown to be very sensitive to which positional isomer is evaluated, as is the organ distribution in rodents. The polyethers had uniformly higher ICE than their corresponding parent ligands in rodents, consistent with in vivo ligand-serum albumin binding studies. Ligand 9 is the most active polyether analogue in rodents and is also very effective in primates, suggesting a higher index of success in humans. In addition, this analogue is also shown to clear more iron in the urine of the primates than many of the other chelators. If this trend were also observed in patients, it would facilitate iron-balance studies in a clinical setting.Humans have evolved a highly efficient iron management system in which we absorb and excrete only about 1 mg of the metal daily; there is no mechanism for the excretion of excess iron. 1 Whether derived from transfused red blood cells 2-4 or from increased absorption of dietary iron, 5,6 without effective treatment, body iron progressively increases with deposition in the liver, heart, pancreas, and elsewhere. Iron accumulation eventually produces (i) liver disease that may progress to cirrhosis, 7-9 (ii) diabetes related both to iron-induced decreases in pancreatic β-cell secretion and increases in hepatic insulin resistance, 10,11 and (iii) heart disease, still the leading cause of death in thalassemia major and related forms of transfusional iron overload. 1,12,13Although 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 ), 14 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; 15,16 higher eukaryotes tend to employ proteins to transport and store iron (e.g., transferrin and ferritin, respectively). 17-19 In humans, nontransferrin-bound plasma iron, a heterogeneous pool of iron *Corresponding Author: Raymond J. Bergeron, Ph.D., Box 100485 JHMHSC, Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, Phone (352) 846-1956, Fax (352) in the circulation that is not bound to the physiological iron transporter, transferrin, seems to be a principal source of iron-mediated o...

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Methoxylation of Desazadesferrithiocin Analogues: Enhanced Iron Clearing Efficiency

Cited by 36 publications

References 56 publications

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

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

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

Impact of the 3,6,9-Trioxadecyloxy Group on Desazadesferrithiocin Analogue Iron Clearance and Organ Distribution

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