Department of Chemistry, Inorganic Chemistry, University of Basel, Spitalstrasse 51, CH-4056, Basel, Switzerland.
Dalton Trans. 2010 Jul 21;39(27):6344-54. doi: 10.1039/c005238h. Epub 2010 Jun 3.
The acidity constants of 3-fold protonated 9-[(2-phosphonomethoxy)ethyl]-2-aminopurine, H(3)(PME2AP)(+), and the stability constants of the M(H;PME2AP)(+) and M(PME2AP) complexes with M(2+) = Ca(2+), Mg(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+) or Cd(2+) have been determined by potentiometric pH titrations in aqueous solution (25 degrees C; I = 0.1 M, NaNO(3)). It is concluded that in the M(H;PME2AP)(+) species, the proton is at the phosphonate group and the metal ion at N7 of the purine residue. This "open" form allows macrochelate formation of M(2+) with the monoprotonated phosphonate residue. The formation degree of this macrochelate amounts on average to 64 +/- 13% (3sigma) for those metal ions for which an evaluation was possible (Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+)). The identity of this formation degree indicates that the M(2+)/P(O)(2)(-)(OH) interaction occurs in an outersphere manner. The application of previously determined straight-line plots of log K(M)(M(R-PO(3)))versus pK(H)(H(R-PO(3))) for simple phosph(on)ate ligands, R-PO(3)(2-), where R represents a residue that does not affect metal ion binding, proves that all the M(PME2AP) complexes have larger stabilities than is expected for a sole phosphonate coordination of M(2+). Combination with previous results allows the following conclusions: (i) The increased stability of the M(PME2AP) complexes of Ca(2+), Mg(2+) and Mn(2+) is due to the formation of 5-membered chelates involving the ether-oxygen atom of the -CH(2)-O-CH(2)-PO(3)(2-) residue; the formation degrees of these M(PME2AP)(cl/O) chelates for the mentioned metal ions vary between about 25% (Ca(2+)) to 40% (Mn(2+)). (ii) For the M(PME2AP) complexes of Co(2+), Ni(2+), Cu(2+), Zn(2+) or Cd(2+) next to the mentioned 5-membered chelates a further isomer is formed, namely a macrochelate involving N7, M(PME2AP)(cl/N7). The formation degrees of these macrochelates vary between about 30% (Cd(2+)) and 85% (Ni(2+)). (iii) The most remarkable observation of this study is that the shift of the NH(2) group from C6 to C2 facilitates very significantly macrochelate formation of a PO(3)(2-)-coordinated M(2+) with N7 due to the removal of steric hindrance in the M(PME2AP) complexes. However, any M(2+) interaction with N3 is completely suppressed, thus leading to significantly different coordination patterns than those observed previously with the antivirally active PMEA(2-) species.
3 倍质子化 9-[(2-膦酸甲酯基)乙基]-2-氨基嘌呤，H(3)(PME2AP)(+)的酸度常数，以及 M(H;PME2AP)(+)和 M(PME2AP)与 M(2+) = Ca(2+)、Mg(2+)、Mn(2+)、Co(2+)、Ni(2+)、Cu(2+)、Zn(2+)或 Cd(2+)的稳定常数，已通过在水溶液中的电位 pH 滴定确定（25°C；I = 0.1 M，NaNO(3)）。结论是，在 M(H;PME2AP)(+)物种中，质子位于膦酸酯基团上，金属离子位于嘌呤残基的 N7 上。这种“开放”形式允许 M(2+)与单质子化的膦酸酯残基形成大环配合物。这种大环配合物的形成程度平均为 64 ± 13%（3σ），对于那些可以进行评估的金属离子（Mn(2+)、Co(2+)、Ni(2+)、Cu(2+)、Zn(2+)）。这个形成程度的同一性表明，M(2+)/P(O)(2-)(OH)相互作用以外壳方式发生。对于简单的磷酸（膦）盐配体 R-PO(3)(2-)，其中 R 代表不影响金属离子结合的残基，先前确定的 log K(M)(M(R-PO(3)))与 pK(H)(H(R-PO(3)))的直线图的应用证明了所有 M(PME2AP)配合物的稳定性都大于预期的 M(2+)仅与磷酸酯配位。结合先前的结果，可以得出以下结论：(i) Ca(2+)、Mg(2+)和 Mn(2+)的 M(PME2AP)配合物稳定性增加是由于形成了涉及-CH(2)-O-CH(2)-PO(3)(2-)残基的醚氧原子的 5 元螯合物；对于提到的金属离子，这些 M(PME2AP)(cl/O)螯合物的形成程度在大约 25%（Ca(2+)）到 40%（Mn(2+)）之间变化。(ii) 对于 Co(2+)、Ni(2+)、Cu(2+)、Zn(2+)或 Cd(2+)的 M(PME2AP)配合物，除了提到的 5 元螯合物外，还形成了另一种异构体，即涉及 N7 的大环螯合物 M(PME2AP)(cl/N7)。这些大环配合物的形成程度在大约 30%（Cd(2+)）到 85%（Ni(2+)）之间变化。(iii) 这项研究最显著的观察结果是，NH(2)基团从 C6 到 C2 的迁移极大地促进了与 PO(3)(2-)配位的 M(2+)与 N7 的大环螯合形成，因为 M(PME2AP)配合物中的空间位阻被消除。然而，任何 M(2+)与 N3 的相互作用都被完全抑制，从而导致与具有抗病毒活性的 PMEA(2-)物种观察到的明显不同的配位模式。
