3-Hydroxy-(4H)-benzopyran-4-ones as potential iron chelating agents in vivo.
Increasing evidence suggests that iron plays an important role in tissue damage both during chronic iron overload diseases (i.e., hemochromatosis) and when, in the absence of actual tissue iron overload, iron is delocalised from specific carriers or intracellular sites (inflammation, neurodegenerative diseases, post-ischaemic reperfusion, etc.). In order to be used for therapeutical purposes in vivo, a reliable iron chelator should be capable of preventing the undesired effects that follow the electrochemical activation of iron (see below). Bearing in mind the molecular structure of some flavonols that are able to chelate iron, we synthesised a new oral iron-chelator, 2-methyl-3-hydroxy-4H-benzopyran-4-one (MCOH). We demonstrate that MCOH chelates iron in a 2:1 ratio showing a stability constant of approximately 10(10). MCOH is able to cross cell membranes (erythrocytes, ascite tumour cells) in both directions. Following intraperitoneal administration to rats, it is quickly taken up by the liver and excreted in the urine within 24h. A similar behaviour has been documented after oral administration. We propose that MCOH may represent the prototype of a new class of iron chelating agents to be developed for iron-removal therapy in vivo with the goal of preventing tissue damage caused by the iron redox cycle.
Ferrali
M
M
Department of Physiopathology and Experimental Medicine, Siena University, via A.Moro, 53100, Siena, Italy. ferrali@unisi.it
Donati
D
D
Bambagioni
S
S
Fontani
M
M
Giorgi
G
G
Pietrangelo
A
A
D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D002867:Chromones / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics*; D015195:Drug Design; D004912:Erythrocytes; D005243:Feces / Q000737:chemistry; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000737:chemistry; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured; D014556:Urine / Q000737:chemistry
D001578:Benzopyrans; D002867:Chromones; D007502:Iron Chelating Agents