Hydrolysis of pyridoxal isonicotinoyl hydrazone and its analogs.
An orally available iron chelator is desirable for the treatment of secondary iron overload. Pyridoxal isonicotinoyl hydrazone (PIH) and its analogs effectively mobilize iron in vivo and in vitro, and are therefore promising candidates for this purpose. PIH analogs undergo significant amino acid-catalyzed hydrolysis in cell culture medium and in serum, achieving equilibrium with their corresponding aldehydes and hydrazides with half-times of 1-8 h. The extent of hydrolysis in RPMI is significant, even in experiments of a few hours' duration, although the half-life of PIH in phosphate-buffered saline (PBS) is approximately 24 h. Therefore, the biological effects (e.g., 59Fe mobilization, toxicity) of these iron chelators have been underestimated in previous studies. Measurement of the affinity of PIH analogs for Fe(3+) under conditions in which hydrolysis is minimal resulted in conditional affinity constants of 10(26) to 10(27) M, which are much lower than predicted by the overall formation constants determined under conditions that likely allowed extensive hydrolysis. These data indicate the importance of hydrolysis of PIH analogs in the interpretation of previous studies, and the importance of designing clinically useful analogs whose efficacies are not limited by hydrolysis.
Buss
Joan L
JL
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 chemin de la Cote-Ste-Catherine, Montreal, Quebec, Canada H3T 1E2.
Ponka
Prem
P
D000818:Animals; D002412:Cations; D002470:Cell Survival; D002478:Cells, Cultured; D015195:Drug Design; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007501:Iron / Q000737:chemistry; D007502:Iron Chelating Agents / Q000737:chemistry*; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D015394:Molecular Structure; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry* / Q000633:toxicity; D012156:Reticulocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D002412:Cations; D007502:Iron Chelating Agents; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D007501:Iron; D007538:Isoniazid