Crystal and molecular structure of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (NIH) and its iron(III) complex: an iron chelator with anti-tumour activity.
Previous studies have demonstrated that 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (NIH) and several other aroylhydrazone chelators possess anti-neoplastic activity due to their ability to bind intracellular iron. In this study we have examined the structure and properties of NIH and its FeIII complex in order to obtain further insight into its anti-tumour activity. Two tridentate NIH ligands deprotonate upon coordination to FeIII in a meridional fashion to form a distorted octahedral, high-spin complex. Solution electrochemistry of [Fe(NIH-H)2]+ shows that the trivalent oxidation state is dominant over a wide potential range and that the FeII analogue is not a stable form of this complex. The fact that [Fe(NIH-H)2]+ cannot cycle between the FeII and FeIII states suggests that the production of toxic free-radical species, e.g. OH. or O2.-, is not part of this ligand's cytotoxic action. This suggestion is supported by cell culture experiments demonstrating that the addition of FeIII to NIH prevents its anti-proliferative effect. The chemistry of this chelator and its FeIII complex are discussed in the context of understanding its anti-tumour activity.
Richardson
D R
DR
Department of Medicine, University of Queensland, Royal Brisbane Hospital, Herston, Australia. D.Richardson@medicine.herston.uq.edu.au
Bernhardt
P V
PV
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004563:Electrochemistry; D006801:Humans; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000188:drug therapy / Q000378:metabolism; D011730:Pyridoxal / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013696:Temperature; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
C120275:2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D007501:Iron; D007538:Isoniazid