Mn2+ Complexes with 12-Membered Pyridine Based Macrocycles Bearing Carboxylate or Phosphonate Pendant Arm: Crystallographic, Thermodynamic, Kinetic, Redox, and 1H/17O Relaxation Studies
Mn2+ Complexes with 12-Membered Pyridine Based Macrocycles Bearing Carboxylate or Phosphonate Pendant Arm: Crystallographic, Thermodynamic, Kinetic, Redox, and 1H/17O Relaxation Studies
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DOI：
10.1021/ic201935r
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发表时间：
2011-12-19
影响因子：
4.6
通讯作者：
Toth, Eva
中科院分区：
文献类型：
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作者：
Drahos, Bohuslav;Kotek, Jan;Toth, Eva
Mn2+配合物代表了Gd3+螯合物的替代品，后者是磁共振成像中广泛使用的造影剂。从这个角度来看，我们研究了两个12元含吡啶的大环配体的Mn2+配合物，它们具有一个垂臂，具有羧酸（HL1）， 6-羧甲基-3,6,9,15-四氮杂环[9.3.1]pentadeca-1(15),11,13-三烯)或膦酸功能（H2L2, 6-二羟基磷基甲基-3,6,9,15-四氮杂环[9.3.1]pentadeca-1(15),11,13-三烯）。这两种配体都是用甲酰基或甲酰基氨基保护基团合成的（从二乙烯三胺或甲酰基二氮吡啶开始）。x射线晶体结构证实了配合物中Mn2+的配位数为6。在水溶液中，这些五齿配体允许一个水分子的自由配位。电位滴定数据表明H2L2的碱度高于HL1，这与带负电荷的膦酸基团的供电子作用有关。根据H-1和（31）pH-NMR滴定测定的质子化序列，前两个质子附着在大环氨基上，而随后的质子化步骤发生在垂臂上。两种配体均与Mn2+形成热力学稳定的配合物，在生理pH和1:1的金属配体比下完全络合。通过与过量Zn2+在不同ph下的反应，研究了其动力学惰性。MnL2的解离是瞬时的（pH值为6时）。对于MnL1，解离非常快(k(obs) = 1-12 x 10(3) s(-1))，比MnDOTA， MnNOTA或15元类似物的Mn2+配合物快得多。它完全通过单质子化络合物的解离进行，不受Zn2+的任何影响。在水溶液中，这两种配合物都是空气敏感的，导致了Mn3+的存在，这是由UV-vis和H-1 NMRD测量和x射线晶体学证明的。循环伏安法测定的氧化峰电位较低（MnL1的E-ox = 0.73 V， MnL2的E-ox = 0.68 V），与空气氧化反应一致。根据不同温度的O-17核磁共振和H-1核磁共振数据确定了控制Mn2+配合物弛豫度的参数。MnL1和MnL2的水交换非常快，k（ex）分别为3.03和1.77 X 10(9) s（-1）。变压O-17核磁共振测量已经被用来评估MnL1和MnL2以及其他Mn2+配合物上的水交换机制。MnL1和MnL2复合物的负活化体积证实了六配位Mn2+离子的水交换结合机制。通过O-17的化学位移，证实了两种配合物的水化数q = 1。磷酸盐、碳酸盐或柠檬酸盐弛豫滴定排除了这些内源性小阴离子对配位水分子的取代。
Mn2+ complexes represent an alternative to Gd3+ chelates which are widely used contrast agents in magnetic resonance imaging. In this perspective, we investigated the Mn2+ complexes of two 12-membered, pyridine-containing macrocyclic ligands bearing one pendant arm with a carboxylic acid (HL1), 6-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene) or a phosphonic acid function (H2L2, 6-dihydroxyphosphorylmethyl-3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene). Both ligands were synthesized using nosyl or tosyl amino-protecting groups (starting from diethylenetriamine or tosylaziridine). The X-ray crystal structures confirmed a coordination number of 6 for Mn2+ in their complexes. In aqueous solution, these pentadentate ligands allow one free coordination site for a water molecule. Potentiometric titration data indicated a higher basicity for H2L2 than that for HL1, related to the electron-donating effect of the negatively charged phosphonate group. According to the protonation sequence determined by H-1 and (31) pH-NMR titrations, the first two protons are attached to macrocyclic amino groups whereas the subsequent protonation steps occur on the pendant arm. Both ligands form thermodynamically stable complexes with Mn2+, with full complexation at physiological pH and 1:1 metal to ligand ratio. The kinetic inertness was studied via reaction with excess of Zn2+ under various pHs. The dissociation of MnL2 is instantaneous (at pH 6). For MnL1), the dissociation is very fast (k(obs) = 1-12 x 10(3) s(-1)), much faster than that for MnDOTA, MnNOTA, or the Mn2+ complex of the 15-membered analogue. It proceeds exclusively via the dissociation of the monoprotonated complex, without any influence of Zn2+. In aqueous solution, both complexes are air-sensitive leading to Mn3+ species, as evidenced by UV-vis and H-1 NMRD measurements and X-ray crystallography. Cyclic voltammetry gave low oxidation peak potentials (E-ox = 0.73 V for MnL1 and E-ox, = 0.68 V for MnL2), in accordance with air-oxidation. The parameters governing the relaxivity of the Mn2+ complexes were determined from variable-temperature O-17 NMR and H-1 NMRD data. The water exchange is extremely fast, k(ex) = 3.03 and 1.77 X 10(9) s(-1) for MnL1 and MnL2, respectively. Variable-pressure O-17 NMR measurements have been performed to assess the water exchange mechanism on MnL1 and MnL2 as well as on other Mn2+ complexes. The negative activation volumes for both MnL1 and MnL2 complexes confirmed an associative mechanism of the water exchange as expected for a hexacoordinated Mn2+ ion. The hydration number of q = 1 was confirmed for both complexes by O-17 chemical shifts. A relaxometric titration with phosphate, carbonate or citrate excluded the replacement of the coordinated water molecule by these small endogenous anions.