Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron-Clearing and Toxicity Profiles

Abstract

Desferrithiocin (DFT, 1) is a very efficient iron chelator when given orally. However, it is severely nephrotoxic. Structure-activity studies with 1 demonstrated that removal of the aromatic nitrogen to provide desazadesferrithiocin (DADFT, 2) and introduction of either a hydroxyl group or a polyether fragment onto the aromatic ring resulted in orally active iron chelators that were much less toxic than 1. The purpose of the current study was to determine if a comparable reduction in renal toxicity could be achieved by performing the same structural manipulations on 1 itself. Accordingly, three DFT analogues were synthesized. Iron clearing efficiency and ferrokinetics were evaluated in rats and primates; toxicity assessments were carried out in rodents. The resulting DFT ligands demonstrated a reduction in toxicity that was equivalent to that of the DADFT analogues and presented with excellent iron clearing properties.

A Base‐ and Metal‐free Protocol for the Synthesis of 2‐Aryl/heteroaryl Thiazolines

“…‐ They form part of many biologically active molecules. For instance, Pyochelin 1 and Desferrithiocin 2 can act as iron chelators and their absence may result in cystic fibrosis, Parkinson's disease, hemorrhagic stroke, cirrhosis and thalassemia . Very recently, polycyclic thiazoline derivatives such as Ulbactin F 3 , isolated from Brevibacillus sp., have shown to inhibit the migration of tumor cells .…”

Iron chelation

“…Several modifications in the chemical structure of the molecule with numerically designated derivatives 2, 3, 6, 7, 8, 9 and 10 have been studied in animals [31,32]. Specifically, each ligand's iron-clearing efficacy (ICE), tissue distribution, biliary ferrokinetics and tissue iron reduction profile are being analyzed in both models.…”

Desferrithiocin: A Search for Clinically Effective Iron Chelators

“…The answer would come with a very simple structural modification of ( S )-4′-(HO)-DADFT-PE ( 34 ): the 3,6,9-trioxadecyloxy polyether moiety was replaced with a 3,6-dioxaheptyloxy function. 168 , 170 , 177 The synthesis involved a 4′- O -alkylation of ( S )-4′-(HO)-DADFT ethyl ester ( 37 ) with polyether tosylate 42 . The ester 43 was next cleaved in base to produce ( S )-4′-(HO)-DADFT-norPE ( 44 ) (Scheme 3 ).…”

“…Accordingly, DFT analogues 46 – 48 were synthesized (Schemes 4 and 5 ). 177 The ICE and ferrokinetics of the ligands were evaluated in rats and primates; toxicity assessments were carried out in rodents. In addition, log P values were also determined.…”

“…Compound 50 was reacted with 4-methoxybenzyl alcohol and K 2 CO 3 in acetonitrile to give the protected diol 51 . Removal of the 4-methoxybenzyl groups of 51 using trifluoroacetic acid (TFA) 177 in pentamethylbenzene 177 at room temperature provided nitrile 52 . Cyclocondensation of 52 with ( S )-2-methyl cysteine ( 2 ) followed by esterification of crude acid 46 with iodoethane and N , N -diisopropylethylamine produced ethyl ( S )-4,5-dihydro-2-(3,5-dihydroxy-2-pyridinyl)-4-methyl-4-thiazolecarboxylate ( 53 ).…”