Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Jul 10;51(13):3913-23.
doi: 10.1021/jm800154m. Epub 2008 Jun 6.

Design, synthesis, and testing of non-nephrotoxic desazadesferrithiocin polyether analogues

Raymond J Bergeron  1 , Jan Wiegand, James S McManis, Neelam Bharti, Shailendra Singh
Affiliations

Design, synthesis, and testing of non-nephrotoxic desazadesferrithiocin polyether analogues

Raymond J Bergeron et al. J Med Chem. .

Abstract

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 micromol/kg/day twice a day (b.i.d.), there was serious proximal tubule damage versus 474 micromol/kg/day once daily (s.i.d.). With 2 and 3, in iron-overloaded and/or non-iron-loaded rodents, kidney histopathologies remained normal.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Dose–response curve – ICE for compounds 1–3 administered po in bile duct-cannulated rats.
Figure 2
Figure 2
Biliary ferrokinetics of 1 in bile duct-cannulated rats. The compounds were administered po.
Figure 3
Figure 3
Biliary ferrokinetics of 2 vs 1 in bile duct-cannulated rats. The compounds were administered po.
Figure 4
Figure 4
Biliary ferrokinetics of 3 vs 1 in bile duct-cannulated rats. The compounds were administered po.
Figure 5
Figure 5
Renal Perfusion. Control (panel A), 1 237 µmol/kg b.i.d × 7 d (panel B), 1 474 µmol/kg s.i.d × 7 d (panel C), 2 237 µmol/kg b.i.d × 7 d (panel D), 3 237 µmol/kg b.i.d × 7 d (panel E). Magnification = 400 ×.
Scheme 1
Scheme 1. Synthesis of 2
aReagents and conditions: (a) K2CO3 (2.1 equiv), acetone, 84%; (b) 50% NaOH (13 equiv), CH3OH, then 1 N HC1, rt, 16 h, 93%.
Scheme 2
Scheme 2. Synthesis of 3
aReagents and conditions: (a) 60% NaH (2.0 equiv), DMSO, 70%; (b) CH3OH (aq), pH 6, 70 °C, 16 h, 90%.
See this image and copyright information in PMC

References

    1. Raymond KN, Carrano CJ. Coordination Chemistry and Microbial Iron Transport. Acc. Chem. Res. 1979;12:183–190. - PMC - PubMed
    1. Bernier G, Girijavallabhan V, Murray A, Niyaz N, Ding P, Miller MJ, Malouin F. Desketoneoenactin-Siderophore Conjugates for Candida: Evidence of Iron Transport-Dependent Species Selectivity. Antimicrob. Agents Chemother. 2005;49:241–248. - PMC - PubMed
    1. Walz AJ, Mollmann U, Miller MJ. Synthesis and Studies of Catechol-Containing Mycobactin S and T Analogs. Org. Biomol. Chem. 2007;5:1621–1628. - PubMed
    1. Yuan WM, Gentil GD, Budde AD, Leong SA. Characterization of the Ustilago Maydis Sid2 GeneEncoding a Multidomain Peptide Synthetase in the Ferrichrome Biosynthetic Gene Cluster J. Bacteriol 20011834040–4051. - PMC - PubMed
    1. Byers BR, Arceneaux JE. Microbial Iron Transport: Iron Acquisition by Pathogenic Microorganisms. Met. Ions Biol. Syst. 1998;35:37–66. - PubMed

Publication types

MeSH terms