title: Influence of ligand structure on Fe(II) spin-state and redox rate in cytotoxic tripodal chelators.
abstract: The Fe coordination chemistry of several tripodal aminopyridyl hexadentate chelators is reported along with cytotoxicity toward cultured Hela cells. The chelators are based on cis, cis-1,3,5-triaminocyclohexane (tach) with three pendant -CH2-2-pyridyl groups where 2-pyridyl is R-substituted thus are named tach-x-Rpyr where x=3, R=Me; x=3, R=MeO; x=6; R=Me. The structures of [Fe(tach-3-Mepyr)]Cl2 and [Fe(tach-3-MeOpyr)](FeCl4) are reported and their metric parameters indicate strongly bound, low-spin Fe(II). The structure of [Fe(tach-6-Mepyr)](ClO4)2 implies steric effects of 6-Me groups push donor Npy's away so one Fe-Npy bond is substantially longer at 2.380(3)A vs. 2.228(3)A for the others, and Fe(II) in the high-spin-state. Accordingly, anions X(-)=Cl or SCN afford [Fe(tach-6-Mepyr)(X)]+ from [Fe(tach-6-Mepyr)]2+ (UV-vis spectroscopy). Consistent with a biological cytotoxicity involving Fe chelation, chelators of low-spin Fe(II) have greater toxicity in the order [IC50(72 h) is in parentheses then the spin-state SS=H (high) or L (low)]: tachpyr=tach-3-Mepyr (6 microM, SS=L) greater, similar tach-3-MeOpyr (12microM, SS=L)>>tach-6-Mepyr (>200 microM, SS=H). Iron-mediated oxidative dehydrogenation with O2 oxidant removes hydrogens from coordinated nitrogen and the adjacent CH2, converting aqueous [Fe(tach-3-Rpyr)]2+ (R=H, Me and MeO) into a mix of low-spin imino- and aminopyridyl-armed complexes, but [Fe(tach-6-Mepyr)]2+ does not react (NMR and ESI-MS spectroscopies). The difference of IC(50) for chelators at different time points (delta IC50=[IC50(24h)-IC50(72 h)]) is used to compare rate of cytotoxic action to qualitative rate of oxidation in the Fe-bound chelator, giving the order, from rapid to slow oxidation and cell killing of: [Fe(tach-3-Mepyr)]2+ (delta IC50=5 microM)>[Fe(tachpyr)]2+ (delta IC50=16 microM)>[Fe(tach-3-MeOpyr)]2+ (delta IC50=118 microM). Thus, those chelators whose Fe(II) complexes undergo rapid oxidation kill cells faster, and those that bind Fe(II) as low-spin are far more cytotoxic.
authors: Department of Chemistry, University of New Hampshire, Durham, NH 03824-3598, USA.
authors: Matt L
authors: ML
authors: Childers
authors: Joonhyung
authors: J
authors: Cho
authors: Celeste A S
authors: CA
authors: Regino
authors: Martin W
authors: MW
authors: Brechbiel
authors: Antonio G
authors: AG
authors: DiPasquale
authors: Arnold L
authors: AL
authors: Rheingold
authors: Suzy V
authors: SV
authors: Torti
authors: Frank M
authors: FM
authors: Torti
authors: Roy P
authors: RP
authors: Planalp
mesh_terms: D000631:Aminopyridines / Q000737:chemistry*; D003514:Cyclohexylamines / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011725:Pyridines / Q000737:chemistry
chemical_list: D000631:Aminopyridines; D003514:Cyclohexylamines; D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D008024:Ligands; D011725:Pyridines; C114047:tachpyr