Childers Matt L, Cho Joonhyung, Regino Celeste A S, Brechbiel Martin W, DiPasquale Antonio G, Rheingold Arnold L, Torti Suzy V, Torti Frank M, Planalp Roy P
Department of Chemistry, University of New Hampshire, Durham, NH 03824-3598, USA.
J Inorg Biochem. 2008 Jan;102(1):150-6. doi: 10.1016/j.jinorgbio.2007.07.039. Epub 2007 Aug 10.
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) are reported and their metric parameters indicate strongly bound, low-spin Fe(II). The structure of Fe(tach-6-Mepyr)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.
报道了几种三脚架型氨基吡啶基六齿螯合剂的铁配位化学及其对培养的Hela细胞的细胞毒性。这些螯合剂基于顺式、顺式-1,3,5-三氨基环己烷（tach），带有三个侧链-CH₂-2-吡啶基，其中2-吡啶基被R取代，因此命名为tach-x-Rpyr，其中x = 3，R = Me；x = 3，R = MeO；x = 6；R = Me。报道了[Fe(tach-3-Mepyr)]Cl₂和Fe(tach-3-MeOpyr)的结构，其度量参数表明存在强结合的低自旋Fe(II)。Fe(tach-6-Mepyr)₂的结构表明6-Me基团的空间效应将供体Npy推开，因此一个Fe-Npy键显著更长，为2.380(3)Å，而其他键为2.228(3)Å，且Fe(II)处于高自旋态。因此，阴离子X⁻ = Cl或SCN可从[Fe(tach-6-Mepyr)]²⁺得到[Fe(tach-6-Mepyr)(X)]⁺（紫外-可见光谱法）。与涉及铁螯合的生物细胞毒性一致，低自旋Fe(II)的螯合剂毒性更大，顺序为[IC₅₀(72 h)在括号内，然后是自旋态SS = H（高）或L（低）]：tachpyr = tach-3-Mepyr（6 μM，SS = L）更大，类似tach-3-MeOpyr（12 μM，SS = L）>> tach-6-Mepyr（>200 μM，SS = H）。以O₂为氧化剂的铁介导氧化脱氢反应从配位氮和相邻的CH₂去除氢，将水溶液中的[Fe(tach-3-Rpyr)]²⁺（R = H、Me和MeO）转化为低自旋亚氨基和氨基吡啶基配位的配合物混合物，但[Fe(tach-6-Mepyr)]²⁺不反应（核磁共振和电喷雾电离质谱光谱法）。螯合剂在不同时间点的IC₅₀差异（ΔIC₅₀ = [IC₅₀(24 h)-IC₅₀(72 h)]）用于比较细胞毒性作用速率与铁配位螯合剂中的氧化定性速率，顺序为从快速氧化和细胞杀伤到缓慢氧化：[Fe(tach-3-Mepyr)]²⁺（ΔIC₅₀ = 5 μM）>[Fe(tachpyr)]²⁺（ΔIC₅₀ = 16 μM）>[Fe(tach-3-MeOpyr)]²⁺（ΔIC₅₀ = 118 μM）。因此，那些Fe(II)配合物经历快速氧化的螯合剂杀死细胞更快，而那些以低自旋形式结合Fe(II)的螯合剂细胞毒性大得多。
