Enhancement of iron excretion via monoanionic 3-hydroxypyrid-4-ones.
The ability of 3-hydroxypyrid-4-ones bearing either a carboxylic acid or sulfonic acid group to mobilize iron into the bile and urine of normal rats has been examined and compared with that produced by 1,2-dimethyl-3-hydroxypyrid-4-one (L1). The compounds tested were 3-hydroxy-1-methyl-4-oxopyridine-6-carboxylic acid and 1-[3-hydroxy-6-(hydroxymethyl)-4-oxopyridyl]-2-ethanesulfonic acid, whose synthesis, biological activity, and X-ray crystallographic properties are described. Although estimates of activity, based on polarity and membrane permeability, predict such compounds to be ineffective, they were found to have an iron-mobilizing ability similar to that of the compounds which do not bear any charge at physiological pH when given parenterally. When given orally, the 3-hydroxypyrid-4-one containing a carboxylate group enhanced the urinary excretion of iron, while the sulfonate analog did not substantially increase the excretion of iron in the urine relative to the controls. The results obtained here suggest that the previous emphasis on the preparation of 3-hydroxypyrid-4-ones that are electrically neutral at physiological pH is unnecessarily restrictive and that the presence of an appropriate group bearing a single negative charge is consistent with a high level of activity. It is proposed that such negatively charged molecules may gain access to the interior of cells in both the kidney and the liver via monoanionic transport systems. Such compounds may prove to be less toxic than the neutral 3-hydroxypyrid-4-ones.
Molenda
J J
JJ
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235.
Jones
M M
MM
Basinger
M A
MA
D000476:Alkanesulfonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000838:Anions; D001646:Bile / Q000378:metabolism*; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005260:Female; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000378:metabolism* / Q000652:urine*; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000476:Alkanesulfonates; D000838:Anions; D002614:Chelating Agents; D011728:Pyridones; C085370:1-(3-hydroxy-6-(hydroxymethyl)-4-oxopyridyl)-2-ethanesulfonic acid; C085371:3-hydroxy-1-methyl-4-oxopyridine-6-carboxylic acid; D007501:Iron