Polyamine-Vectored Iron Chelators:  The Role of Charge

Bergeron, Raymond J.; Bharti, Neelam; Wiegand, Jan; McManis, James S.; Hua, Yuexuan; Prókai, László

doi:10.1021/jm048974f

Cited by 22 publications

(34 citation statements)

References 87 publications

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“…5 In the course of developing N -alkylated analogues of the natural polyamines as anticancer drugs, 6,7 the structural boundary conditions set by the polyamine transporter on these substrates were defined. All of the findings, 8,9 are consistent with the idea that charge is critical to transporter recognition of the polyamine analogues. We have in fact been able to successfully exploit the polyamine transport apparatus in delivering iron chelators intracellularly.…”

supporting

confidence: 81%

“…Furthermore, concentrations of ≈ 3000 µM of the free acid adduct 4 were seen in these same cells, obviously deriving from nonspecific serum esterase hydrolysis of the parent ester 5 . 9 Interestingly, the polyamine ester adduct 5 competed well for the polyamine transporter, K i 5.7 µM, while the acid conjugate 4 did not, K i 73 µM. In keeping with the idea, negatively charged cargo fragments fixed to polyamine vectors, for example, the carboxylate of 4 at physiologic pH, are not well transported.…”

mentioning

confidence: 83%

“…The norspermidine adducts, ( S )-4,5-dihydro-2-[2-hydroxy-4-(12-amino-5,9-diazadodecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid ( 4 ) and its ester ( 5 ) (Table 1) were thus assembled and evaluated. 9 …”

mentioning

confidence: 99%

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Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators

Bergeron¹,

Singh²,

Bharti³

et al. 2010

Synthesis

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Iron chelators have been shown to control the growth of cancer cells in culture by sequestering exogenous iron in the media. Thus, the ligands prevent cellular access to the metal. However, because transferrin provides iron to tumor cells in animals, chelators have not been effective antitumor agents. Polyamine chelator conjugates in which the polyamine vectored ligands into cells were far more active than the free chelators themselves. However, the free ligands were not released from the vector once in the cell. The current study focuses on the synthesis and preliminary evaluation of a polyamine chelator conjugate capable of releasing the free ligand intracellularly via a nonspecific esterase.

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supporting

confidence: 81%

mentioning

confidence: 83%

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Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators

Bergeron¹,

Singh²,

Bharti³

et al. 2010

Synthesis

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“…In the present work, selective alkylation of ethyl ester 4 48 was accomplished by heating tosylate 5 (1.3 equiv) and potassium carbonate (2.1 equiv) in acetone, providing masked chelator 6 in 84% yield (Scheme 1). Cleavage of ethyl ester 6 as before afforded 2 in 93% yield.…”

Section: Synthesismentioning

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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“…Potassium carbonate (2.76 g, 20.0 mmol) and KI (200 mg, 1.2 mmol) were added to a mixture of 15 [82] (2.81 g, 10 mmol) in DMF (100 mL). A solution of 16 (1.24 g, 10 mmol) in DMF (10 mL) was added to the reaction mixture, which was heated at 100 °C for 24 h. After cooling to room temperature, H 2 O (100 mL) was added followed by extraction with EtOAc (2 × 100 mL).…”

Section: Methodsmentioning

confidence: 99%

Metabolically programmed iron chelators

Bergeron

Bharti

McManis

et al. 2015

Bioorganic & Medicinal Chemistry

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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.

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Polyamine-Vectored Iron Chelators: The Role of Charge

Cited by 22 publications

References 87 publications

Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators

Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators

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

Metabolically programmed iron chelators

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