Desazadesmethyldesferrithiocin Analogues as Orally Effective Iron Chelators

Abstract

Further structure-activity studies of desferrithiocin analogues are carried out. (S)-Desazadesmethyldesferrithiocin, 2-(2-hydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid, serves as the principal framework in the current paper. Desazadesmethyldesferrithiocin can be structurally altered with facility, and data are already available on its iron-clearing properties and toxicity parameters. Four different kinds of structural modifications of this framework are undertaken: introduction of hydroxy, carboxy, or methoxy groups on the aromatic ring; alteration of the thiazoline ring; increasing the distance between the ligand donor atoms; and benz-fusion of the aromatic rings. The structural modifications described are shown to have a tremendous impact on both the iron clearance and toxicity profiles of the desazadesmethyldesferrithiocin molecule. All of the compounds are assessed in a bile-duct-cannulated rodent model to determine iron clearance efficiency. Ligands which demonstrate an efficiency of greater than 2% are carried forward to the iron-overloaded primate for iron-clearing measurements. Ligands with efficiencies greater than 3% in the primate are then evaluated in a formal toxicity study in rodents. On the basis of the results of the present work, 2-(2, 4-dihydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid is a promising candidate for clinical evaluation.

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

“…5). Even when administered subcutaneously, the efficiency was not observed to increase (Bergeron et al, 1999b). From these results it can be hypothesized that the poor activity of these analogs was not due to bioavailability but rather that these modifications altered the optimum spacing needed for chelation, reducing their iron-binding capabilities.…”

“…In contrast, a decrease in iron chelation efficacy of DMDFT was observed in the Cebus apella primate model compared with DFT . Although the efficiency of this analog was below that of DFT, this ligand was found to exhibit no toxic side effects when orally administered on a daily basis to rodents in a 30-day trial (Bergeron et al, 1999b). Interestingly, this dramatic shift in toxicity was simply due to the removal of the thiazoline methyl group.…”

“…Hence, other DFT analogs, including (S)-desazadesferrithiocin (DADFT; (Bergeron et al, 1999a,b). Unfortunately, both DADFT and DADMDFT were found to elicit severe gastrointestinal toxicity during rodent trials (Bergeron et al, , 1999b. Despite their adverse side effects, DADFT and DADMDFT have acted as critical intermediate structures during the SAR examination of this series of iron chelators.…”

“…Subsequent structural investigations into the distances between the donor groups of DADMDFT revealed that this scaffold could not be altered without the loss of iron-binding ability (Bergeron et al, 1999b). The addition of a methylene group between the two rings of the scaffold or either one or two methylene groups between the carboxyl and thiazoline ring resulted in poor orally active analogs (Fig.…”

HBED ligand: preclinical studies of a potential alternative to deferoxamine for treatment of chronic iron overload and acute iron poisoning

“…Fecal and urine samples were collected at 24-hour intervals and processed as given in detail in earlier publications [32][33][34]38 before analysis by flame atomic absorption.…”