The impact of polyether chain length on the iron clearing efficiency and physiochemical properties of desferrithiocin analogues.
(S)-2-(2,4-Dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (2) was abandoned in clinical trials as an iron chelator for the treatment of iron overload disease because of its nephrotoxicity. However, subsequent investigations revealed that replacing the 4'-(HO) of 2 with a 3,6,9-trioxadecyloxy group, ligand 4, increased iron clearing efficiency (ICE) and ameliorated the renal toxicity of 2. This compelled a closer look at additional polyether analogues, the subject of this work. The 3,6,9,12-tetraoxatridecyloxy analogue of 4, chelator 5, an oil, had twice the ICE in rodents of 4, although its ICE in primates was reduced relative to 4. The corresponding 3,6-dioxaheptyloxy analogue of 2, 6 (a crystalline solid), had high ICEs in both the rodent and primate models. It significantly decorporated hepatic, renal, and cardiac iron, with no obvious histopathologies. These findings suggest that polyether chain length has a profound effect on ICE, tissue iron decorporation, and ligand physiochemical properties.
Department of Medicinal Chemistry University of Florida, Gainesville, Florida 32610-0485, USA.
Raymond J
RJ
Bergeron
Neelam
N
Bharti
Jan
J
Wiegand
James S
JS
McManis
Shailendra
S
Singh
Khalil A
KA
Abboud
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism; D002428:Cebus; D055598:Chemical Phenomena; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D004986:Ether / Q000737:chemistry; D004987:Ethers / Q000737:chemistry*; D006801:Humans; D007501:Iron / Q000302:isolation & purification* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D019190:Iron Overload / Q000378:metabolism; D007668:Kidney / Q000187:drug effects; D008024:Ligands; D008297:Male; D000442:Octanols / Q000737:chemistry; D051381:Rats; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014867:Water / Q000737:chemistry
D004095:Dihydropyridines; D004987:Ethers; D007502:Iron Chelating Agents; D008024:Ligands; D000442:Octanols; D013844:Thiazoles; D014867:Water; D004986:Ether; D007501:Iron; C050223:desferrithiocin