Methylenediphosphonotetrathioate: Synthesis, characterization, and chemical properties

Article abstract of DOI:10.1021/ic3026057

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 10⁷ 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 (IC ₅₀ 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_¹/2 = 71.5 h) and basic media (pD 12.4, t_¹/2 = 81 h) as monitored by ³¹P/¹H 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.