Department of Chemistry, Bar Ilan University, Ramat-Gan 52900, Israel.
Inorg Chem. 2013 Mar 18;52(6):3133-40. doi: 10.1021/ic3026057. Epub 2013 Mar 1.
Metal chelators are potential therapeutic agents for treating diseases such as Wilson's and Alzheimer's where the pathology involves an excess of metal-ions (Cu(II) and Zn(II)/Cu(II)/Fe(II/III), respectively). In addition to the high affinity of the metal-ion to the chelators, metal selectivity of the chelators is essential to achieve the therapeutic goal, that is, the successful removal of excess of harmful metal-ions in a physiological extracellular medium rich in alkali and alkali earth metal-ions. For this purpose, we synthesized a novel chelator, methylenediphosphonotetrathioate (MDPT) which is the tetrathio analogue of methylenediphosphonic acid (MDP). MDPT was synthesized from bis-methylene(phosphonicdichloride) in a 3-step synthesis and a 31% overall yield. MDPT formed a stable complex with Zn(II) (log K = 10.84), which is 10(7) times more stable than the corresponding Ca(II) complex. Moreover, the MDPT-Zn(II) complex was 50-fold more stable than the MDP-Zn(II) complex. In addition, MDPT was found to inhibit the Cu(I)-catalyzed Fenton reaction (IC50 26 μM) 2.5 times more potently than a Fe(II)-catalyzed Fenton reaction, and 2.5 times more potently than EDTA (IC50 64 μM) in the Cu(I)/H2O2 system, as monitored by electron spin resonance (ESR). Furthermore, MDPT was found to be relatively stable in both acidic (pD 1.9, t(½) = 71.5 h) and basic media (pD 12.4, t(½) = 81 h) as monitored by (31)P/(1)H NMR. However, MDPT was not stable in air because of intramolecular oxidation and disulfide formation (33% oxidation after 27 h). In conclusion, MDPT was found to be a water-soluble chelator showing a clear preference to soft/borderline metal-ions and a remarkable selectivity to those metal-ions vs Ca(II) ions. The relative sensitivity of MDPT to oxidation may limit its use; however, the application of MDPT in acidic or basic media will increase its lifetime.
金属螯合剂是治疗威尔逊病和阿尔茨海默病等疾病的潜在治疗药物，这些疾病的病理学涉及过量的金属离子（Cu(II)和 Zn(II)/Cu(II)/Fe(II/III)）。除了金属离子与螯合剂的高亲和力外，螯合剂的金属选择性对于实现治疗目标至关重要，即成功去除富含碱和碱土金属离子的生理细胞外介质中过量的有害金属离子。为此，我们合成了一种新型螯合剂，亚甲基二膦四硫代酯（MDPT），它是亚甲基二膦酸（MDP）的四硫代类似物。MDPT 是由双亚甲基（膦二氯）经过三步合成法合成的，总收率为 31%。MDPT 与 Zn(II)形成稳定的配合物（log K = 10.84），比相应的 Ca(II)配合物稳定 10(7)倍。此外，MDPT-Zn(II)配合物比 MDP-Zn(II)配合物稳定 50 倍。此外，研究发现 MDPT 抑制 Cu(I)-催化的芬顿反应（IC50 为 26 μM）的能力比 Fe(II)-催化的芬顿反应强 2.5 倍，比 EDTA（IC50 为 64 μM）强 2.5 倍，在 Cu(I)/H2O2 体系中通过电子自旋共振（ESR）监测。此外，通过 (31)P/(1)H NMR 监测发现，MDPT 在酸性（pD 1.9，t(½) = 71.5 h）和碱性介质（pD 12.4，t(½) = 81 h）中都相对稳定。然而，由于分子内氧化和二硫化物形成，MDPT 在空气中不稳定（27 小时后氧化 33%）。综上所述，MDPT 是一种水溶性螯合剂，对软/边界金属离子有明显的偏好，对这些金属离子相对于 Ca(II)离子有显著的选择性。MDPT 对氧化的相对敏感性可能会限制其应用；然而，在酸性或碱性介质中应用 MDPT 将增加其寿命。
