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

Abstract

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...

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

“…Because of the significant serum albumin binding of 1 in rodents, unlike what was seen with the 4'-polyether 2, the saturable nature of iron clearance is likely overshadowed. 46 At 300 and 150 µmol/kg, the iron clearance of 1 was virtually over by 9-12 h ( Figure 2). At both doses, >98% of the ligand-induced iron excretion occurred in the bile.…”

“…When rodents were given 3 po at 300 µmol/kg (Table 1), the drug caused the excretion of nearly twice as much iron as 2, 0.887 ± 0.367 mg Fe/kg and had an ICE of 10.6 ± 4.4% 46 ( Figure 1). Iron clearance persisted much longer for 3 than for 2, and was not complete until nearly 24 h postdrug (Figure 4).…”

“…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).…”

“…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). 45,47 Polyether 2, in which a 3,6,9-trioxadecyl group was fixed to the 4'-hydroxy of 1, performed significantly better at 300 µmol/kg, with an ICE of 5.5 ± 1.9% when administered po (p < 0.003 vs 1).…”

“…45 Polyether 3 given po at 75 µmol/kg, presented an ICE of 24.5 ± 7.6%. 46 a b.i.d., twice a day; DFO, desferrioxamine B mesylate; DFT, desferrithiocin [(S)-4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylic acid]; ICE, iron-clearing efficiency; s.i.d., once a day While earlier studies carried out in rodents clearly demonstrated 2 to be less nephrotoxic than the parent drug 1, 45 the toxicity profile of 3 was not evaluated, nor were any dose-response studies carried out with any of the ligands to assess how such manipulation impacts on ICE and toxicity. The new synthetic schemes described below now make ligands 2 and 3 more readily accessible and make further biological evaluation possible.…”