(<i>S</i>)-4,5-Dihydro-2-(2-hydroxy-4-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic Acid Polyethers:  A Solution to Nephrotoxicity

Bergeron, Raymond J.; Wiegand, Jan; McManis, James S.; Vinson, J. R. Timothy; Hua, Yuexuan; Bharti, Neelam; Rocca, James R.

doi:10.1021/jm0508944

Cited by 20 publications

(250 citation statements)

References 49 publications

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“…These results are virtually identical to what we had published previously. 45 However, when 1 was given once daily at the same total dose, 474 µmol/kg/day for 7 days, although there was some vacuolization of the proximal tubule cells ( Figure 5C), the damage was much less severe than when the drug was given twice daily ( Figure 5B). Interestingly, and much to our surprise, besides some inclusion bodies seen when either 2 or 3 were given at 237 µmol/kg b.i.d.…”

Section: A Comparison Of the Impact Of 1 2 And 3 On Rodent Kidneysmentioning

confidence: 94%

“…When 1 was given to rats at a dose of 300 µmol/kg either po or sc 45 (Table 2), the ICE numbers were very low and within error 1.1 ± 0.8% (po) and 1.1 ± 0.6% (sc, p >0.05). The corresponding polyether 2 at the same dose, 300 µmol/kg, either po (5.5 ± 1.9%) or sc (8.7 ± 2.6%) 45 had ICE values that were also within error (p > 0.05).…”

Section: Iron-clearing Efficiency In Non-iron-overloaded Rodents and mentioning

confidence: 96%

“…45 This study led to the less lipophilic, more water-soluble ligand, the polyether (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (2). 45 A subsequent study assessing the impact of introducing the 3,6,9-trioxadecyloxy group at various positions of the desazadesferrithiocin aromatic ring 46 revealed the 3'-polyether analogue [(S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (3 , Table 1) to also be an orally active iron chelator. 46 The ICE of 1 in a non-iron-overloaded rodent model after oral (po) administration at 300 µmol/kg was shown to be 1.1 ± 0.8% (Table 1).…”

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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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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: A Comparison Of the Impact Of 1 2 And 3 On Rodent Kidneysmentioning

confidence: 94%

Section: Iron-clearing Efficiency In Non-iron-overloaded Rodents and mentioning

confidence: 96%

mentioning

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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“…39 Recall that iron clearing efficiency (ICE) is defined as (net iron excretion)/(total iron-binding capacity of the chelator), expressed as a percent. The relative ICE values of compounds 1 and 2 were in keeping with their log P app values: the more lipophilic, the larger log P app , the more efficient the chelator.…”

Section: We Previously Demonstrated That In the (S)-4′-(ho)-dadft Sermentioning

confidence: 99%

“…39 Initial kidney tissue level measurements taken at 2 h from animals treated with the 4′-polyether (3) seemed consistent with the histopathology; there was less polyether in the kidney than the parent drug and less nephrotoxicity. 39 The ICE in both rodents and primates and the absence of toxicity seen with the 4-polyether (3) compelled us to investigate the impact of fixing the 3,6,9-polyether chain to the aromatic ring of DADFT at positions other than the 4′-carbon had on ICE and ligand tissue distribution. Two systems were chosen, (S)-3′-(HO)-DADFT-PE (9) and (S)-5′-(HO)-DADFT-PE (6) ( Tables 1 and 2).…”

Section: Chelator Tissue Distribution In Rodentsmentioning

confidence: 99%

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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Biological and Biomedical Aspects of Metal Phenolates

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2014

Patai's Chemistry of Functional Groups

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The phenol functionality is involved in diverse biological processes and functions, serving as a proton donor and as a metal‐binding ligand. It is commonly found in many biochemicals (such as siderophores and the amino acids tyrosine and tryptophan), pharmaceuticals (including antibiotics, metal‐chelating agents, and diagnostic agents), and natural products (such as polyphenols, flavonoids, and salicylic acid). In association with other functional groups, the phenol moiety forms various types of metal‐binding sites of diverse structures and functions, for example, for iron binding and transport, in enzymes for oxygenation of substrates, and for biotransformation of aromatic compounds. Many environmentally hazardous aromatic compounds such as bisphenol A, PCB, and DDT can be degraded by tyrosinate(phenolate)‐containing metalloenzymes from microorganisms, which provides a clue for bioremediation of these toxic substances. Moreover, the phenol‐containing wet‐adhesive byssal proteins from some clams and mussels has stimulated further development of adhesive materials for medical and other applications; and the study of binding of transferrin with nanoparticles affords better understanding of protein–mineral interfacial interactions. In addition to these naturally occurring metal‐phenolate centers, there are many metal complexes of phenol and derivatives that exhibit various catalytic activities and serve as structural and/or functional model systems for tyrosinate‐containing metalloproteins.

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(S)-4,5-Dihydro-2-(2-hydroxy-4-hydroxyphenyl)-4-methyl-4-thiazolecarboxylic Acid Polyethers: A Solution to Nephrotoxicity

Cited by 20 publications

References 49 publications

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

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

Biological and Biomedical Aspects of Metal Phenolates

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