Influence of ligand structure on Fe(II) spin-state and redox rate in cytotoxic tripodal chelators

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) Å vs. 2.228(3) Å 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 μM, SS = L) ≳ tach-3-MeOpyr (12 μM, SS = L) ≫ tach-6-Mepyr (>200 μM, 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 IC50 for chelators at different time points (ΔIC50 = [IC50(24 h) − 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+ (ΔIC50 = 5 μM) > [Fe(tachpyr)]2+ (ΔIC50 = 16 μM) > [Fe(tach-3-MeOpyr)]2+ (ΔIC50 = 118 μM). 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.