Structure-Activity Relationships Among Desazadesferrithiocin Analogues

Bergeron, Raymond J.; Wiegand, Jan; McManis, James S.; Weimar, William R.; Huang, Guangfei

doi:10.1007/978-1-4615-0593-8_9

Cited by 11 publications

(10 citation statements)

References 44 publications

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“…Ligands were assembled that achieved high levels in the organs most affected in iron overload diseases, i.e., liver, pancreas, and heart. The magnitude of the structure−activity investigation required to achieve this goal was not insignificant. − This work coupled with previous DFT structure−activity exploration underscores the need for a more universal tool for delivering iron chelators intracellularly, not just desferrithiocin analogues, but chelators in general. Thus, the current paper further explores the utility of polyamines as vectors for enhanced intracellular delivery of iron chelators.…”

Section: Introductionmentioning

confidence: 89%

Polyamine-Vectored Iron Chelators: The Role of Charge

et al. 2005

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The utility of polyamines as vectors for the intracellular transport of iron chelators is further described. Consistent with earlier results with polyamine analogues, these studies underscore the importance of charge in the design of polyamine-vectored chelators. Four polyamine conjugates are synthesized, two of terephthalic acid [N(1)-(4-carboxy)benzoylspermine (7) and its methyl ester (6)] and two of (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT] [(S)-4,5-dihydro-2-[2-hydroxy-4-(12-amino-5,9-diazadodecyl-oxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (10) and its ethyl ester (9)]. These four molecules were evaluated in murine leukemia L1210 cells for their impact on cell proliferation (48- and 96-h IC(50) values), their ability to compete with spermidine for the polyamine transport apparatus (K(i)), and their intracellular accumulation. The data revealed that when neutral molecules (cargo fragments) were fixed to the polyamine vector, the conjugates competed well with spermidine for transport and were accumulated intracellularly to millimolar levels. However, this was not the case when the cargo fragments were negatively charged. Metabolic studies of the polyamine-vectored (S)-4'-(HO)-DADFTs in rodents indicated that not only did the expected deaminopropylation step occur, but also a surprisingly high level of oxidative deamination at the terminal primary nitrogens took place. Finally, the iron-clearing efficiency of the (S)-4'-(HO)-DADFT conjugates was determined in a bile-duct-cannulated rodent model. Attaching the ligand to a polyamine vector had a profound effect on increasing the iron-clearing efficiency of this chelator relative to its parent drug.

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Section: Introductionmentioning

confidence: 89%

Polyamine-Vectored Iron Chelators: The Role of Charge

et al. 2005

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“…Desferrithiocin (DFT) [2-(3-hydroxypyridin-2-yl)-4-methyl-4,5-dihyrothiazole-4-carboxylic acid; Fig. 4] is a tridentate siderophore from the bacterium Streptomyces antibioticus DSM 1865 (for reviews, see Bergeron et al, 2002;Brittenham, 2003;Nick et al, 2003). This ligand binds iron through its phenolic oxygen, carboxylate oxygen, and thiazole nitrogen donor atoms (Brittenham, 2003).…”

Section: A Siderophoresmentioning

confidence: 99%

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

2005

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“…These efforts have led to the identification of several interesting compounds, a few of which may be of possible clinical use. The most outstanding of these compounds, in addition to deferiprone, are pyridoxal isonicotinoyl hydrazone (PIH),31 bishydroxyphenyl thiazole (ICL670),32 and desferrithiocin (DFT) 33. The results of detailed pharmacokinetic studies and of large‐scale clinical evaluation of ICL670 are now available and will be presented at this meeting.…”

Section: New Oral Chelatorsmentioning

confidence: 99%

Objectives and Mechanism of Iron Chelation Therapy

Hershko

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Konijn

et al. 2005

Annals of the New York Academy of Sciences

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Prevention of cardiac mortality is the most important beneficial effect of iron chelation therapy. Unfortunately, compliance with the rigorous requirements of daily subcutaneous deferoxamine (DFO) infusions is still a serious limiting factor in treatment success. The development of orally effective iron chelators such as deferiprone and ICL670 is intended to improve compliance. Although total iron excretion with deferiprone is somewhat less than with DFO, deferiprone may have a better cardioprotective effect than DFO due to deferiprone's ability to penetrate cell membranes. Recent clinical studies indicate that oral ICL670 treatment is well tolerated and is as effective as parenteral DFO used at the standard dose of 40 mg/kg of body weight/day. Thus, for the patient with transfusional iron overload in whom results of DFO treatment are unsatisfactory, several orally effective agents are now available to avoid serious organ damage. Finally, combined chelation treatment is emerging as a reasonable alternative to chelator monotherapy. Combining a weak chelator that has a better ability to penetrate cells with a stronger chelator that penetrates cells poorly but has a more efficient urinary excretion may result in improved therapeutic effect through iron shuttling between the two compounds. The efficacy of combined chelation treatment is additive and offers an increased likelihood of success in patients previously failing DFO or deferiprone monotherapy.

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Structure-Activity Relationships Among Desazadesferrithiocin Analogues

Cited by 11 publications

References 44 publications

Polyamine-Vectored Iron Chelators: The Role of Charge

Polyamine-Vectored Iron Chelators: The Role of Charge

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

Objectives and Mechanism of Iron Chelation Therapy

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