NOVEL IRON COMPLEXES AND CHELATORS BASED ON CIS,CIS-1,3,5-TRIAMINOCYCLOHEXANE - IRON-MEDIATED LIGAND OXIDATION AND BIOCHEMICAL-PROPERTIES

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 (refer red to as tachpyr) gives rise to six-coordinate, low-spin, cationic co mplexes of Fe(II). Tachpyr also displays a cytotoxicity toward culture d bladder cancer cells that is believed to involve coordination of int racellular iron. The anaerobic reaction of tachpyr with Fe(II) salts a ffords the Fe(II)-tachpyr(2+) complex, but in presence of oxygen, oxid ative dehydrogenation of one or two of the aminomethylene group(s) of the ligand occurs, with formal loss of H-2: R-N(H)-C(H)(2)-(2-py) --> R-N = C(H) - (2-py) + H-2. The resulting mono- and diimino Fe(II) comp lexes (denoted as [Fe(tachpyr-H-2)](2+) and [Fe(tachpyr-2H(2))](2+)) a re an inseparable mixture, but they may be fully oxidized by H2O2 to t he known tris (imino) complex Fe(II) [cis,cis-1,3,5-tris (pyridine-2-c arboxaldimino)cyclohexane](2+) (or [Fe(tachpyr-3H(2))](2+)). Cyclic vo ltammetry of the imino complex mixture reveals an irreversible anodic wave at +0.78 V vs. NHE. Tachpyr acts as a reducing agent toward Fe(II II) salts, affording the same two Fe(II) imino complexes as products. Tachpyr also reductively removes Fe(III) from an Fe(III)(ATP)(3) compl ex (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 m etal affinity through in creased steric hindrance, and preventing Fe(I II) reduction because oxidative dehydrogenation of nitrogen is blocked . The N-methyl tachpyr derivative binds Fe(II) only weakly as a high-s pin complex, and no complexation or reduction of Fe(III) is observed. Corresponding to their inability to bind iron, the N-alkylated chelato rs are nontoxic to cultured bladder cancer cells. A tach-based chelato r 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, a nd cytotoxicity.