CSIRO PUBLISHING Full Paper www.publish.csiro.au/journals/ajc Aust. J. Chem. 2007, 60, 685–690 Bisamidoximes: Synthesis and Complexation with Iron(III) James E. Johnson, A,E Carol Carvallo, A Debra D. Dolliver, B Natalia Sanchez, A Vilma Garza, A Diana C. Canseco, A Gordon L. Eggleton, C and Frank R. Fronczek D A Department of Chemistry and Physics,Texas Woman’s University, Denton,TX 76204-5859, USA. B Department of Chemistry and Physics, Southeastern Louisiana University, Hammond, LA 70402, USA. C Department of Physical Sciences, Southeastern Oklahoma University, Durant, OK 74701-0609, USA. D Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA. E Corresponding author. Email: jjohnson@mail.twu.edu Bisamidoximes have been synthesized by the reaction of 4-methylbenzohydroximoyl chloride with 1,2-diaminoethane, 1,3-diaminopropane, 1,4-diaminobutane, and 3,3 ′ -diamino-N-methyl-dipropylamine. A monoamidoxime and a trisami- doxime were also prepared in the present work by the reaction of 4-methylbenzohydroximoyl chloride with N,N- dimethylethylenediamine and tris(2-aminoethyl)amine. Single crystal X-ray structures of three of the bisamidoximes have shown that the two amidoxime moieties have the Z configuration in all three compounds. Job’s method of continuous variations showed that three of the bisamidoximes prepared in this work form 1:1 complexes with iron(iii) and therefore are acting as tetradentate ligands. Manuscript received: 17 May 2007. Final version: 1 August 2007. Introduction Although iron is essential for most forms of life, the low solu- bility of ferric hydroxide in water has necessitated sophisticated mechanisms for the transport and management of iron(iii) in bio- logical systems. Microorganisms often use low molecular weight chelators (siderophores) to solubilize and transport ferric ion. Siderophores commonly contain the hydroxamic acid functional group, which forms hexacoordinate, octahedral complexes with ferric ion. [1,2] Humans have developed a complex iron storage and recy- cling process to supply the ferric ion necessary for proper cell function. Unfortunately, humans afflicted with certain genetic disorders, such as thalassemia and aplastic anemia, must receive periodic transfusions, which lead to excess iron in the body. [3] Excess iron in this closed metabolic loop leads to chronic over- load and to peroxidative tissue damage. For these iron overload syndromes, the treatment of choice has been chelation therapy. Specifically, an open-chain siderophore (desferrioxamine B, 1, DFO, Scheme 1), which forms a 1:1 hexacoordinate, octahedral H 2 N N N HO O O H N N OH O O H N OH O 1 N N O OH H O H 2 (SAHA) Scheme 1. complex with iron(iii), has been the primary chelator used to rid the body of iron in these overload syndromes. [4] Although it has been proved to be effective and to display good long-term tolerability, it is expensive and relatively inefficient. [3–5] Recently, it has been discovered that hydroxamic acids can be used as histone deacetylase (HDAC) inhibitors. These com- pounds have antiproliferative activity and have been shown to be useful therapeutic agents. [6–8] Octanedioic acid hydroxyamide phenylamide (2, suberoylanilide hydroxamic acid, SAHA, Scheme 1) has recently received US Food and Drug Admin- istration approval for the treatment of advanced cutaneousT-cell lymphoma. [8b] An important feature of the HDAC inhibitors is their ability to complex the zinc ion in the active site. [8d] It is apparent then that other types of metal chelators should be investigated as alternative therapies for the removal of ferric ion in iron overload syndromes and as potential HDAC inhibitors. The present paper reports on a new and improved route for the synthesis of bisamidoximes (3d–g, Scheme 2). Whereas 3a and 3b have been previously synthesized through a seven-step route, [9] the procedure described herein is a relatively simple three-step route that begins with 4-methylbenzaldehyde.As ami- doximes are known to form coloured complexes with transition metals including iron(iii), [10,11b] the ability of these bisami- doximes to complex with iron(iii) has also been investigated. Results and Discussion The bisamidoximes were synthesized by treating various diamines with a benzohydroximoyl chloride (4, Scheme 2). The hydroximoyl chloride was prepared by reaction of a ben- zaldoxime with N-chlorosuccinimide according to a literature procedure. [12] © CSIRO 2007 10.1071/CH07157 0004-9425/07/090685