Effects of C-4 stereochemistry and C-4' hydroxylation on the iron clearing efficiency and toxicity of desferrithiocin analogues.
Additional structure-activity studies of desferrithiocin analogues are carried out. The effects of stereochemistry at C-4 on the ligands' iron clearing efficiency are reviewed and assessed using the enantiomers 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(R)-carboxylic acid and 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid. The utility of 4'-hydroxylation as a method of reducing the toxicity of desazadesferrithiocin analogues is also examined further with the synthesis and in vivo comparison of 4, 5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, which is the natural product 4-methylaeruginoic acid, and 4, 5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid. The stereochemistry at C-4 is shown to have a substantial effect on the iron clearing efficiency of desferrithiocin analogues, as does C-4'-hydroxylation on the toxicity profile. All of the compounds are evaluated in a bile-duct-cannulated rodent model to determine iron clearance efficiency and are carried forward to the iron-overloaded primate for iron clearing measurements. On the basis of the results of the present work, although 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid is still the most promising candidate for clinical evaluation, 4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid (4'-hydroxydesazadesferrithiocin) also merits further preclinical assessment.
Bergeron
R J
RJ
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610-0485, USA.
Wiegand
J
J
McManis
J S
JS
McCosar
B H
BH
Weimar
W R
WR
Brittenham
G M
GM
Smith
R E
RE
D000818:Animals; D001646:Bile / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002428:Cebus; D006900:Hydroxylation; D007501:Iron / Q000378:metabolism* / Q000652:urine; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
C120073:4'-hydroxydesazadesferrithiocin; C120074:4,5-dihydro-2-(2,4-dihydroxphenyl)thiazole-4-carboxylic acid; D002264:Carboxylic Acids; D007502:Iron Chelating Agents; D008024:Ligands; D013844:Thiazoles; D007501:Iron