Partition-Variant Desferrithiocin Analogues:  Organ Targeting and Increased Iron Clearance

Abstract

Altering the lipophilicity (log P(app)) of desferrithiocin analogues can change the organ distribution of the chelators and lead to enhanced iron clearance. For example, alkylation of (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT] and its analogues to more lipophilic compounds, such as (S)-4,5-dihydro-2-(2-hydroxy-4-methoxyphenyl)-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(CH3O)-DADFT], provides ligands that achieved between a 3- and 8-fold increase in chelator concentrations in the heart, liver, and pancreas (the organs most at risk in iron-overload disease) of treated rodents. The 4'-O-methylated compounds are demethylated to their hydroxylated counterparts in rodents; furthermore, this O-demethylation takes place in both rodent and human liver microsomes. The relationship between chelator lipophilicity and iron-clearing efficacy in the iron-overloaded Cebus apella primate is further underscored by a comparison of the iron-clearing efficiency of (S)-2-(2,3-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT] and its 3'-(CH3O) counterpart. Finally, these DFT analogues are shown to be both inhibitors of the iron-mediated oxidation of ascorbate as well as effective radical scavengers.

The Design, Synthesis, and Evaluation of Organ-Specific Iron Chelators

“…The previous studies with ligands [1,2] and [7,8] clearly indicated that the more lipophilic chelators had greater ICE values. 43 In the current study with [3,4] and [9,10], again the more lipophilic ligand was the more efficient (4 > 3, p < 0.001 and 10 > 9, p < 0.003). While the polyether (6) follows the expected trend, the dimethoxy systems 5 and 11 were not well behaved within the DADFT and DADMDFT families; their ICEs were higher than anticipated.…”

A Comparative Study of the Synthesis of 3‐Substituted Catechols using an Enzymatic and a Chemoenzymatic Method

“…Catechols C [R = Cl, Br, I, Me, CF 3 CH(OH)], isolated during this study, showed identical physical and spectral characteristics to those reported. [2,3,7,40] (À)-cis-(1S,2R)-3-Methyl-3-cyclohexene-1,2-diol D (R = Me) Biotransformation Using P. putida UV4 to Yield cisDihydrodiols B Biotransformation procedures employed for arene substrates A (including 1,5-D 2 -and D 8 -toluene) with whole cells of P. putida UV4, a proprietary constitutive mutant strain derived from the wild type strain P. putida NCIB 11767, were identical to those reported earlier for the production of cis-dihydrodiols B. [3,12,35,36] Biotransformation Using E. coli nar B to Yield Catechols C E. coli nar B was grown at 37 8C in Luria broth (LB) medium.…”

Synthesis of Acinetobactin

“…Oxazolidine 13 was afforded by the reaction of a L-threonine derivative with 12, [8][9][10] which was derived from 10. Carboxylic acid 14 11) was afforded in 80% yield by the hydrogenolysis of 13.…”