Gyungse Park

Novel iron complexes and chelators based on cis,cis-1,3,5-triaminocyclohexane: iron-mediated ligand oxidation and biochemical properties

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.

Effect of metal size on coordination geometry of N,N′,N″-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane: synthesis and structure of [MIIL](ClO4)2 (M=Zn, Cd and Hg)

Abstract The hexadentate ligand N , N ′, N ″-tris(2-pyridylmethyl)- cis , cis -1,3,5-triaminocyclohexane (tachpyr) forms stable metal complexes from the salts M(ClO 4 ) 2 ·6H 2 O (M=Zn 2+ and Cd 2+ ) and Hg(ClO 4 ) 2 in methanol or ethanol. The complexes [Zn(tachpyr)](ClO 4 ) 2 ·CH 3 OH ( 1 ·CH 3 OH), [Cd(tachpyr)](ClO 4 ) 2 ( 2 ) and [Hg(tachpyr)](ClO 4 ) 2 ( 3 ) have been isolated, and their solid state structures have been determined and analyzed. The coordination sphere changes from octahedral to trigonal-prismatic geometry with increasing metal radius. The trigonal twist angles ( α ) are 43.7(2)° in compound 1 ·CH 3 OH, range between 11.0(4)° and 21.7(2)° in compound 2 and range between 3.1(3)° and 5.5(2)° in compound 3 . To accommodate larger metal ions there is also a slight outward expansion of the triaminocyclohexane nitrogens, which leads to a reduction in the average cyclohexyl ring C–C–C–C torsion angles ( β ) with concomitant flattening of the ring. The torsion angles ( β ) in 1 ·CH 3 OH are 52.3(6)° and 52.4(6)°, range between 46.1(9)° and 52.7(9)° in compound 2 and range between 45.1(6)° and 52.9(7)° in compound 3 .

IRON CHELATION IN CANCER THERAPY

There is a large body of experimental and clinical literature that attests to the importance of iron in tumor cell growth. High levels of dietary iron have been linked epidemiologically to the increased development of tumors in man;1,2 dietary iron increases the rate of tumor formation in experimental animals.3–5 Although these observations may in part reflect the role of iron in tumor initiation through the generation of oxygen free radicals, there is abundant evidence that an iron-rich environment contributes to enhanced tumor cell growth. For example, administration of iron-dextran to mice inoculated with leukemia cells dramatically enhanced leukemic cell proliferation; at the higher levels of supplemental iron, the leukemic animals died 25% faster than controls.6 In a study of subcutaneously implanted tumors in three strains of mice maintained on a low or normal iron supplemented diet, the low iron diet resulted in less rapid tumor growth.7 Similar observations have been made in spontaneous mammary tumors in rats.8