Novel iron complexes and chelators based on cis,cis-1,3,5-triaminocyclohexane: iron-mediated ligand oxidation and biochemical properties |
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| Authors: | G Park F H Lu N Ye M W Brechbiel S V Torti F M Torti R P Planalp |
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| Institution: | (1) Department of Chemistry, University of New Hampshire, Durham, NH 03824-3598, USA e-mail: roy.planalp@unh.edu, Tel.: +1-603-862-2471, Fax: +1-603-862-4278, US;(2) Radiation Oncology Branch, National Institutes of Health, Bethesda, MD 20892, USA, US;(3) Department of Biochemistry,;(4) Department of Cancer Biology and Internal Medicine, Wake Forest University School of Medicine, Bowman Gray Campus and the Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC 27157, USA, US |
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| Abstract: | The interaction of Fe(II) and Fe(III) with the novel Fe(II) chelator N,N′N″-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (referred to as tachpyr) gives rise to six-coordinate, low-spin, cationic complexes of Fe(II).
Tachpyr also displays a cytotoxicity toward cultured bladder cancer cells that is believed to involve coordination of intracellular
iron. The anaerobic reaction of tachpyr with Fe(II) salts affords the Fe(II)-tachpyr2+ complex, but in presence of oxygen, oxidative dehydrogenation of one or two of the aminomethylene group(s) of the ligand
occurs, with formal loss of H2: R—N(H)—C(H)2—(2-py) → R—N=C(H)—(2-py)+H2. The resulting mono- and diimino Fe(II) complexes (denoted as Fe(tachpyr-H2)]2+ and Fe(tachpyr-2H2)]2+) are an inseparable mixture, but they may be fully oxidized by H2O2 to the known tris(imino) complex Fe(II)cis,cis-1,3,5-tris(pyridine-2-carboxaldimino)cyclohexane]2+ (or Fe(tachpyr-3H2)]2+). Cyclic voltammetry of the imino complex mixture reveals an irreversible anodic wave at +0.78 V vs. NHE. Tachpyr acts as
a reducing agent toward Fe(IIII) salts, affording the same two Fe(II) imino complexes as products. Tachpyr also reductively
removes Fe(III) from an Fe(III)(ATP)3 complex (which is a putative form of intracellular iron), producing the two Fe(II) imino complexes. Novel N-alkylated derivatives of tachpyr have been synthesized. N-Alkylation has two effects on tachpyr: lowering metal affinity through increased steric hindrance, and preventing Fe(III)
reduction because oxidative dehydrogenation of nitrogen is blocked. The N-methyl tachpyr derivative binds Fe(II) only weakly as a high-spin complex, and no complexation or reduction of Fe(III) is
observed. Corresponding to their inability to bind iron, the N-alkylated chelators are nontoxic to cultured bladder cancer cells. A tach-based chelator with three N-propyleneamino arms is also synthesized. Studies of the chemical and biochemical properties of this chelator further support
a relationship between intracellular iron chelation, iron reduction, and cytotoxicity.
Received: 23 March 1998 / Accepted: 1 June 1998 |
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| Keywords: | Iron complexes Chelating agents Iron metabolism Oxidative dehydrogenation Cytotoxicity |
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