title: Desferrithiocin analogues and nephrotoxicity.
abstract: The syntheses of a series of 4'-O-alkylated ( S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazole-carboxylic acid and 5'-O-alkylated ( S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, log P(app), is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of log P(app) versus ICE in a rodent model for both the 4'-O-alkylated 2,4-dihydroxy and 5'-O-alkylated 2,5-dihydroxy series produced an inverse parabola plot with r(2) values of 0.97 and 0.81, respectively. The plots indicate an optimum log P(app)/ICE relationship. Because of the nature of the data spread in the 4'-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties?
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA. rayb@ufl.edu
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Bergeron
authors.forename: Jan
authors.initials: J
authors.lastname: Wiegand
authors.forename: James S
authors.initials: JS
authors.lastname: McManis
authors.forename: Neelam
authors.initials: N
authors.lastname: Bharti
authors.forename: Shailendra
authors.initials: S
authors.lastname: Singh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002428:Cebus; D004095:Dihydropyridines / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D019190:Iron Overload / Q000188:drug therapy / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013844:Thiazoles / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D004095:Dihydropyridines; D007502:Iron Chelating Agents; D008024:Ligands; D008055:Lipids; D013844:Thiazoles; D014867:Water; D007501:Iron; C050223:desferrithiocin
references.citation: Alcohol. 2003 Jun;30(2):151-8
references.pmid: 12957300
references.citation: J Med Chem. 2006 Nov 30;49(24):7032-43
references.pmid: 17125256
references.citation: Pharmacol Rev. 2005 Dec;57(4):547-83
references.pmid: 16382108
references.citation: Clin Liver Dis. 2000 May;4(2):409-29, vi-vii
references.pmid: 11232198
references.citation: Blood. 1998 Jan 1;91(1):295-300
references.pmid: 9414297
references.citation: J Lab Clin Med. 2001 May;137(5):324-9
references.pmid: 11329529
references.citation: Blood. 1992 Apr 1;79(7):1882-90
references.pmid: 1558978
references.citation: Acta Haematol. 1996;95(1):37-48
references.pmid: 8604585
references.citation: Met Ions Biol Syst. 1998;35:37-66
references.pmid: 9444759
references.citation: J Biol Chem. 1984 Mar 25;259(6):3620-4
references.pmid: 6323433
references.citation: J Med Chem. 2003 Apr 10;46(8):1470-7
references.pmid: 12672247
references.citation: Semin Hematol. 2001 Oct;38(4):360-6
references.pmid: 11605171
references.citation: J Med Chem. 1999 Jan 14;42(1):95-108
references.pmid: 9888836
references.citation: J Med Chem. 2007 Jul 12;50(14):3302-13
references.pmid: 17564424
references.citation: Lancet. 1989 Jul 1;2(8653):27-30
references.pmid: 2567801
references.citation: J Clin Pharmacol. 2003 Jun;43(6):565-72
references.pmid: 12817519
references.citation: Best Pract Res Clin Haematol. 2005 Jun;18(2):289-98
references.pmid: 15737891
references.citation: Blood. 1993 Apr 15;81(8):2166-73
references.pmid: 8471775
references.citation: Bioorg Med Chem. 2003 Nov 3;11(22):4693-711
references.pmid: 14556785
references.citation: J Med Chem. 1999 Jul 1;42(13):2432-40
references.pmid: 10395484
references.citation: Baillieres Clin Haematol. 1989 Apr;2(2):323-43
references.pmid: 2660931
references.citation: J Med Chem. 1996 Apr 12;39(8):1575-81
references.pmid: 8648596
references.citation: J Biol Chem. 1998 Feb 27;273(9):4997-5005
references.pmid: 9478947
references.citation: Acc Chem Res. 2015 Sep 15;48(9):2496-505
references.pmid: 26332443
references.citation: N Engl J Med. 1998 Aug 13;339(7):417-23
references.pmid: 9700174
references.citation: N Engl J Med. 2000 Aug 3;343(5):327-31
references.pmid: 10922422
references.citation: Blood. 2004 Sep 1;104(5):1519-25
references.pmid: 15155457
references.citation: J Med Chem. 2008 Jul 10;51(13):3913-23
references.pmid: 18533709
references.citation: N Engl J Med. 1994 Sep 1;331(9):567-73
references.pmid: 8047080
references.citation: J Med Chem. 2005 Jun 16;48(12):4120-37
references.pmid: 15943485
references.citation: Am J Med Sci. 1999 Oct;318(4):213-29
references.pmid: 10522550
references.citation: Br J Haematol. 1968 Feb;14(2):119-29
references.pmid: 5638259
references.citation: Semin Hematol. 2001 Jan;38(1 Suppl 1):14-22
references.pmid: 11206956
references.citation: Blood. 1998 Feb 15;91(4):1446-52
references.pmid: 9454776
references.citation: Nat Med. 2003 Sep;9(9):1187-94
references.pmid: 12937413
references.citation: Lancet. 2003 May 10;361(9369):1597-602
references.pmid: 12747879
references.citation: Blood. 1997 Feb 1;89(3):739-61
references.pmid: 9028304
references.citation: Adv Exp Med Biol. 2002;509:19-43
references.pmid: 12572987
references.citation: Ann N Y Acad Sci. 1990;612:378-93
references.pmid: 2127168
references.citation: Eur J Pediatr. 2003 Mar;162(3):139-146
references.pmid: 12655415
references.citation: J Med Chem. 1991 Jul;34(7):2072-8
references.pmid: 2066978
references.citation: Ann Hematol. 1996 Nov;73(5):247-52
references.pmid: 8959943
references.citation: Can J Gastroenterol. 2002 May;16(5):297-302
references.pmid: 12045778
references.citation: Free Radic Biol Med. 1992;13(2):169-81
references.pmid: 1355459
references.citation: Toxicol Appl Pharmacol. 1967 May;10(3):481-500
references.pmid: 4964684
references.citation: Nutr Rev. 1994 Aug;52(8 Pt 1):253-65
references.pmid: 7970288
references.citation: Mol Aspects Med. 2001 Feb-Apr;22(1-2):1-87
references.pmid: 11207374
references.citation: Curr Med Chem. 2003 Jun;10(12):1065-76
references.pmid: 12678677
references.citation: J Med Chem. 2006 May 4;49(9):2772-83
references.pmid: 16640338
references.citation: Chem Rev. 2003 Nov;103(11):4207-82
references.pmid: 14611263