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 isonicot inoyl hydrazone (NIH) and several other aroylhydrazone chelators possess an ti-neoplastic activity due to their ability to bind intracellular iron. In this study we have examined the structure and properties of NIH and its Fe- III complex in order to obtain further insight into its anti-tumour activit y. Two tridentate NIH ligands deprotonate upon coordination to Fe-III in a meridional fashion to form a distorted octahedral, high-spin complex. Solut ion electrochemistry of [Fe(NIH-H)(2)](+) shows that the trivalent oxidatio n state is dominant over a wide potential range and that the Fe-II analogue is not a stable form of this complex. The fact that [Fe(NIH-H)(2)](+) cann ot-cycle between the Fe-II and Fe-III states suggests that the production o f toxic free- radical species, e.g. OH. or O2(.-),is not part of this ligan d's cytotoxic action. This suggestion is supported by cell culture experime nts demonstrating that the addition of Fe-III to NIH prevents its anti-prol iferative effect. The chemistry of this chelator and its Fe-III complex are discussed in the context of understanding its anti-tumour activity.