Structure/activity relationships affecting the ability of monoanionic 3-hydroxyprid-4-ones to mobilize iron.
Current attempts to remove iron from individuals suffering from iron overload have encountered difficulty due to the toxicity of the administered chelating agent. In a search for iron chelators of potentially reduced toxicity, nine monoanionic compounds have been examined. To determine the chemical features which govern their ability to induce the excretion of iron, the compounds were administered to female Sprague-Dawley rats. All carboxylate derivatives were tested for biliary excretion following iv injection, as well as for urinary excretion following iv or po injection. Sulfonate derivatives were tested for biliary and urinary excretion as well, but only one representative compound was tested po. The biological activity of the new pyridinones was compared to that of 1,2-dimethyl-3-hydroxypyrid-4-one, L1, which served as the standard. While none of the chelators was able to surpass L1 in both urinary and biliary iron excretion, all of the chelators at least equaled L1 in one of these two areas following iv administration. Two derivatives surpassed the standard in mobilizing iron into the bile, and all others were statistically equivalent. In terms of urinary excretion, two compounds were equivalent to L1 after iv administration, although none of the compounds equaled L1 when administered orally. The structure of (1,4-dihydro-3-hydroxy-2-methyl-4-oxo-1- pyridyl)methanecarboxylic acid was determined by X-ray diffraction, as this compound showed higher activity than previously reported by other investigators. We speculate that these chelators utilize organ-specific, monoanionic transport systems in the liver and kidneys to mobilize iron and that their toxicity may be substantially less than that of their neutral analogs.
Molenda
J J
JJ
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
Jones
M M
MM
Cecil
K M
KM
Basinger
M A
MA
D000818:Animals; D002614:Chelating Agents / Q000737:chemistry / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D005260:Female; D007501:Iron; D011728:Pyridones / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013054:Spectrophotometry, Atomic; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D007501:Iron