title: Methylenediphosphonotetrathioate: synthesis, characterization, and chemical properties.
abstract: 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.
authors: Department of Chemistry, Bar Ilan University, Ramat-Gan 52900, Israel.
authors: Aviran
authors: A
authors: Amir
authors: Alon Haim
authors: AH
authors: Sayer
authors: Alon
authors: A
authors: Ezra
authors: Bilha
authors: B
authors: Fischer
mesh_terms: D000388:Air; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D017665:Hydroxyl Radical / Q000737:chemistry; D009946:Organothiophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D010084:Oxidation-Reduction; D010757:Phosphorous Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
chemical_list: D000975:Antioxidants; D002614:Chelating Agents; D009946:Organothiophosphorus Compounds; D010757:Phosphorous Acids; D014867:Water; C570063:phosphonic acid; D017665:Hydroxyl Radical; D015032:Zinc; D002118:Calcium