Methylenediphosphonic Acid Research Articles

Synthesis of new functionalized mono‐ and diphosphonic acids with five‐membered aza‐heterocycles moieties

AbstractThe new functionalized hydroxymethylphosphonic and methylenediphosphonic acids are synthesized via unique reaction of tris(trimethylsilyl)phosphite and N‐formyl derivatives of five‐membered aza‐heterocycles at the presence of effective catalyst—trimethylsilyl triflate.

Synthesis of new functionalized aryl‐substituted methylphosphonic and methylenediphosphonic acids and their derivatives

AbstractThe convenient syntheses of new aryl‐substituted hydroxymethylphosphonic and methylenediphosphonic acids from the aromatic aldehydes, their derivatives, and phosphorous acid esters in the presence of the effective catalysts (trimethylsilyl trifluoromethanesulfonate, zinc chloride, and cadmium iodide) were developed.

Multiple-Step Humidity-Induced Single-Crystal to Single-Crystal Transformations of a Cobalt Phosphonate: Structural and Proton Conductivity Studies.

Humidity-induced multiple-step single-crystal to single-crystal (SC-SC) transformations are observed in the cobalt phosphonate (NH4)3[Co2(bamdpH)2(HCOO)(H2O)2] (1), where bamdpH4 is (benzylazanediyl)bis(methylene)diphosphonic acid, [C6H5CH2N(CH2PO3H2)2]. Under high-humidity conditions (95% RH), compound 1 experiences hydrolysis at 60 °C which is accompanied by the transformation from a double-chain structure of compound 1 into a single-chain structure of [Co(bamdpH2)(H2O)2]·2H2O (2). When the humidity is below 10% RH, part of the lattice water in compound 2 can be released, forming a third phase, [Co(bamdpH2)(H2O)2]·H2O (3). The structural transformation processes have been monitored by infrared and proton conductivity measurements.

New amino bisphosphonate compound for skeletal imaging: Comparison study with methylenediphosphonic acid (MDP) and (1-hydroxyethane-1,1-diyl) diphosphonic acid (HEDP)

Abstract A novel bisphosphonate derivative (1-aminoethane-1,1-diyl)diphosphonic acid (AEDP) has been prepared and successfully labeled with 99mTc at high labeling yields. The in vivo biodistribution of 99mTc-AEDP has been investigated and compared with two reference compounds Tc-99m methylene diphosphonate (99mTc-MDP) and Tc-99m (1-hydroxyethylidene) diphosphonate (99mTc-HEDP). The biodistribution studies have demonstrated a high uptake of the radiotracer 99mTc-AEDP in the bone and a rapid clearance from the blood (such as the two technetium-labeled bone imaging agents in current use: 99mTc-MDP and 99mTc-HEDP). Additionally, the scintigraphic images of 99mTc-AEDP in normal rats have revealed high selective skeletal uptake.

Synthesis of Substituted N‐Formylaminomethylenediphosphonates and Their Derivatives

ABSTRACTThe convenient methods for the synthesis of new trimethylsilyl esters of aminomethylenediphosphonic acids are elaborated. The new substituted N‐formylaminomethylenediphosphonates are obtained via the interaction of trimethylsilyl esters of methylenediphosphonic acids with a mixture of triethyl orthoformate and ethanol. Also boron trifluoride–diethyl etherate as an effective catalyst is used for the interaction of hydrochlorides of ethoxymethylene imines with diethyl trimethylsilyl phosphite. The corresponding aminomethylenediphosphonic acids are presented.

TU-F-CAMPUS-I-02: Phosphorus Metabolite Differences Between Type 2 Diabetic and Normal Skeletal Muscle

Purpose: Type 2 diabetes mellitus (T2DM) is implicated with impaired ATP production in skeletal muscle. Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) was used to measure the baseline concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP) in the vastus lateralis (VL) muscle. Methods: Six T2DM subjects (6 male, age = 51±12) and three normal glucose tolerant (NGT) subjects (2 male, age = 40±16) were studied. A slice-selective 31P-MRS sequence (TR=10s, TE=2.3 ms, NSA=16, 25mm slice) was performed to determine the absolute concentrations, [PCr], [Pi], [ATP]. After the legs were scanned, a leg phantom (15 cm diameter, 4 L cylinder with 35 mM phosphoric acid (H₃PO₄)), was scanned using the same slab positioning. A 6 mL vial with 850 mM of methylenediphosphonic acid (MDP)) was the external reference standard. The tissue volumes were calculated from a five-slice MRI scan. The jMRUI software package was used to measure the areas under spectral peaks. A two-tailed t-test was performed, with significance deemed as p<0.05. Results: The subjects with T2DM had an average absolute [PCr] = 24.9±4.5 mM while for the NGT subjects [PCr] = 31.9±1.9 mM. The t-test showed a significant difference (p=0.04) between the means of the two groups. There was no significant difference between the means for [Pi] and [ATP] between T2DM and NGT subjects. For all nine subjects the average and standard deviation of [Pi] and [ATP] were 2.86±0.45 mM and 6.99±1.30 mM, respectively. Conclusion: Subjects with T2DM have lower baseline values of PCr than subjects with normal glucose tolerance. This has not been previously reported and the mechanisms for this need to be studied further. Future studies will investigate the PCr utilization under exercise conditions. Funding: NIH K Grant 1K25DK089012.

Synthetic-method-dependent magnetic relaxation in a cobalt(II) phosphonate chain compound.

A polar cobalt(II) phosphonate Co(bamdpH2)(H2O) (1) [bamdpH4 = (benzylazanediyl)bis(methylene)diphosphonic acid] is reported. It shows a linear chain structure. The neighboring chains are connected by moderately strong hydrogen bonds forming a supramolecular layer. The interlayer spaces are filled with the organic groups of the phosphonate ligands. Compound 1 displays the coexistence of single-chain magnet behavior and canted antiferromagnetism below 2.8 K. Moreover, the magnetic dynamics is strongly dependent on the synthetic methods, a phenomenon that has not been documented before.

The Road to Functional Lanthanide-Phosphonate Metal-Organic Frameworks

The endless possible combination of metal centers and organic ligands renders the field of Metal-Organic Frameworks (MOFs) an extremely rich playground for the design of new functional materials. The symbiotic co-existence of organic and inorganic components in these compounds embody the final products with unusual properties, which may, for example, ally photoluminescence with catalysis and even thermal robustness for more advanced technological applications. Our research group has focused on the development of functional MOFs based on rare-earth cations and polyphosphonate organic ligands, many of which designed and prepared in our laboratories. This poster summarizes the synthesis, structural elucidation and photophysical and catalytic properties of the novel one- (1D) and three-dimensional (3D) materials prepared using the tripodal (benzene-1,3,5-triyltris(methylene))triphosphonic acid (H6bmt) and the bipodal 1,4-phenylenebis(methylene)diphosphonic acid (H4pmd) organic ligands: [Ln(H4bmt)(H5bmt)(H2O)2]·3H2O (system 1: 1D), [Ln2(H3bmt)2(H2O)2]·H2O (system 2: 3D), and [Ln(Hpmd)(H2O)] (system 3: 3D) (please note: Ln stands for a rare-earth cation) [1-3]. System 1 is an outstanding heterogeneous catalyst in the methanolysis of styrene oxide at nearly room temperature, even outperforming the well-known nano-sized HKUST-1 MOF material. System 2 exhibits unusual photoluminescent properties: the Tb-containing material has an absolute emission quantum yield of ca. 46%; for the Eu-containing compound this value is easily increased from ca. 15% to 54% by removing, under vacuum, all water molecules in the material, this being only possible due to its typical zeolitic behaviour. System 3 can be prepared in large quantitites as either micro- or nano-sized crystals, with the latter exhibiting a remarkable high heterogeneous catalytic activity. Fundação para a Ciência e a Tecnologia (FCT, Portugal; EXPL/CTM-NAN/0013/2013 - FCOMP-01-0124-FEDER-041282), Bruker AXS (Karlsruhe, Germany), the European Union, QREN, FEDER, COMPETE and Laboratório Associado CICECO (PEst-C/CTM/LA0011/2013) are gratefully acknowledged for funding the research and the dissemination of the results. The presenting author also wishes to thank all the collaborators involved in the referenced publications.

Infrared Spectroscopy in Cancer Diagnosis and Chemotherapy Monitoring

We demonstrate that IR spectroscopic analysis can be used in diagnosis and chemotherapy monitoring for cancers of various organs at the molecular level. We used Fourier transform IR spectroscopy to study human breast and thyroid tumor tissues which were removed during surgery. The characteristic frequencies of C = O stretching vibrations in the IR spectra of tissues of pathological foci were compared with data from histological examination. In the IR spectra of healthy tissues or for benign tumors, the most intense absorption bands ν(C = O) are located in the interval 1675–1650 cm–1. When malignant neoplasms are present in the organs, the intensity of the bands in this range of the spectrum is reduced, while the intensities of the absorption bands in the 1710–1680 cm–1 interval increase. We also studied lung tissue for mice of the C57B1/6 line for healthy tissue and after implantation of B-16 melanoma tumor. The IR spectra of healthy mouse lung tissue and mouse lung tissue with B-16 melanoma metastases in the region of the C = O stretching vibrations display the same differences. We found that when lung malignancy was treated with the optimal dose of a synthesized drug based on palladium complexes of methylenediphosphonic acid, the spectroscopic signs of the presence of metastases in the lungs disappear, and the IR spectrum of the lung tissue after treatment practically coincides with the spectrum of healthy lung tissue.

Three New Silver Uranyl Diphosphonates: Structures and Properties

The hydrothermal reaction of uranium trioxide and methylenediphosphonic acid in the presence of silver nitrate resulted in the formation of three new uranyl coordination polymers: AgUO2[CH2(PO3)(PO3H)] (Ag-1), [Ag2(H2O)1.5]{(UO2)2[CH2(PO3)2]F2}·(H2O)0.5 (Ag-2), and Ag2UO2[CH2(PO3)2] (Ag-3). All consist of uranyl pentagonal bipyramids that form two-dimensional layered structures. Ag-1 and Ag-3 possess the same structural building unit, but the structures are different; Ag-3 is formed through edge-sharing of F atoms to form UO5F2 dimers. The pH and silver cation have significant effects on the structure that is synthesized. Raman spectra of single crystals of Ag-1, Ag-2, and Ag-3 reveal v1 UO2(2+) symmetric stretches of 816 and 829, 822, and 802 cm(-1), respectively. Electronic structure calculations were performed using the projector augmented wave (PAW) method with density functional theory (DFT) to gain insight into the nature of bonding and electronic characteristics of the synthesized compounds. Herein, we report the syntheses, crystal structures, Raman spectroscopy, and luminescent behavior of these three compounds.

Gas Sorption Studies on a Microporous Coordination Polymer Assembled from 2D Grid Layers by Strong π-π Interactions

The microporous coordination polymer [Co(H2 L)(bipy)0.5 ]⋅2 H2 O (1, bipy=4,4'-bipyridine) was synthesized on the basis of the V-shaped flexible diphosphonate ligand (2,4,6-trimethyl-1,3-phenylene)bis(methylene)diphosphonic acid (H4 L) and the auxiliary bipy ligand under hydrothermal conditions. The structure of this compound was characterized by single-crystal X-ray diffraction. By joining the diphosphonate ligands and bipy through tetrahedral [CoO3 N] clusters, a 2D square grid layered network was formed. Further stacking of these layers on the basis of π-π interactions resulted in a pseudo-3D microporous network with 1D channels running through the a axis. Gas sorption studies for CO2 , H2 , CH4 , N2 , and O2 on this coordination polymer were performed, and the results revealed interesting dynamic and hysteresis sorption behavior toward H2 at low temperature.

Metal-organic frameworks based on uranyl and phosphonate ligands

Three new crystalline metal-organic frameworks have been prepared from the reaction of uranyl nitrate with nitrilotris(methylphosphonic acid) [H6nmp, N(CH2PO3H2)3], 1,4-phenylenebis(methylene)diphosphonic acid [H4pmd, C6H4(PO3H2)2], and (benzene-1,3,5-triyltris(methylene))triphosphonic acid [H6bmt, C6H3(PO3H2)3]. Compound [(UO2)2F(H3nmp)(H2O)]·4H2O (I) crystallizes in space group C2/c, showing two crystallographically independent uranyl centres with pentagonal bipyramidal coordination geometries. While one metal centre is composed of a {(UO2)O3(μ-F)}2 dimer, the other comprises an isolated {(UO2)O5} polyhedron. Compound [(UO2)(H2pmd)] (II) crystallizes in space group P21/c, showing a centrosymmetric uranyl centre with an octahedral {(UO2)O4} coordination geometry. Compound [(UO2)3(H3bmt)2(H2O)2]·14H2O (III) crystallizes in space group P\bar 1, showing two crystallographically independent uranyl centres. One uranyl centre is a {(UO2)O5} pentagonal bipyramid similar to that in (I), while the other is a {(UO2)O4} centrosymmetric octahedron similar to that in (II). Compounds (I) and (III) contain solvent-accessible volumes accounting for ca 23.6 and 26.9% of their unit-cell volume, respectively. In (I) the cavity has a columnar shape and is occupied by disordered water molecules, while in (III) the cavity is a two-dimensional layer with more ordered water molecules. All compounds have been studied in the solid state using FT-IR spectroscopy. Topological studies show that compounds (I) and (III) are trinodal, with 3,6,6- and 4,4,6-connected networks, respectively. Compound (II) is instead a 4-connected uninodal network of the type cds.

Salt Tolerance Enhancement of Liquid Chromatography-Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry Using Matrix Additive Methylenediphosphonic Acid.

Mass spectrometry (MS) is a highly sensitive analytical technique that is often coupled with liquid chromatography (LC). However, some buffering salts used in LC (e.g., phosphate and tris(hydroxymethyl)aminomethane (Tris)) are incompatible with MS since they cause ion-source contamination and signal suppression. In this study, we examined salt tolerance of MALDI and applied a matrix additive methylenediphosphonic acid (MDPNA) to reduce salt-induced signal suppression. MDPNA significantly improved the salt tolerance of MALDI-MS. Using ammonium formate buffer at pH 5.0, the effective range of buffering salt concentration in MALDI-MS using MDPNA was estimated up to 250 mM. MDPNA reduced signal suppression caused by buffering salts at pH 4.0 to 8.0. We observed that MDPNA effectively worked over a wide range of buffer conditions. MDPNA was further applied to hydrophilic interaction chromatography (HILIC) and chromatofocusing-MALDI-MS. As a result, the analytes in the eluent containing high-concentration salts were detected with high sensitivity. Thus, our study provides simple and fast LC-MALDI-MS analysis technique not having strict limitation of buffering condition in LC by using matrix additive MDPNA.

Solution Phosphorus-31 Nuclear Magnetic Resonance Spectroscopy of Soils from 2005 to 2013: A Review of Sample Preparation and Experimental Parameters

Phosphorus nuclear magnetic resonance (³¹P NMR) spectroscopy is an important tool for the study of soil P and has significantly advanced our knowledge of soil P forms, particularly organic P; however, it must be used correctly to provide meaningful results. This review covers the ³¹P NMR studies of soil published from 2005 to 2013. The first part discusses preparing samples for ³¹P NMR, including extractants, pre- and post-extraction treatments, the physical state of the soil sample at the time of extraction, extraction length, the soil/extractant ratio, P recovery, P in residues, methods to concentrate extracts, redissolving samples for ³¹P NMR experiments, the use of the internal standard methylene diphosphonic acid, and the potential for degradation with any of these steps. The second part of this review focuses on NMR experiment parameters, including delay times, proton decoupling, and experiment length. Potential concerns in these areas are noted, and suggestions are given for procedures to optimize the information obtained from a ³¹P NMR experiment.

Synthesis, Structures, and Properties of Two Novel Coordination Polymers with a V‐shaped Diphosphonate Ligand

AbstractTwo novel coordination polymers, [Cu(H2L)(bipy)(H2O)2]·H2O (1) and [Ni2(H2L)(bipy)2.5(H2O)6]·(H2L)·7H2O (2) with the V‐shaped diphosphonate ligand (2,4,6‐trimethyl‐1,3‐phenylene)bis(methylene)diphosphonic acid (H4L) were synthesized via hydrothermal reactions in the presence of auxiliary ligand 4,4′‐bipyridine. Their structures were determined by single‐crystal X‐ray diffraction and further characterized by elemental analysis, infrared spectroscopy (IR), and thermogravimetric analysis (TGA). Compound 1 crystallizes in the Pnma space group and compound 2 crystallizes in the P21212 space group. They display square‐grid layer and bilayer two‐dimensional network, respectively.

A tetranuclear oxofluorovanadium(IV) cluster encapsulating a Na(H2O)n+ subunit

Hydrothermal reactions of sodium vanadate, methylenediphosphonic acid, hydrogen fluoride and the appropriate organoamine yielded the vanadium(IV)-oxyfluoride compounds [NH3(CH2)2(NH2)(CH2)2NH3]3[{Na(H2O)} ⊂ {V4O4F2(O3PCH2PO3)4}]·8H2O (1·8H2O) and [NH3(CH2)2(NH2)(CH2)2(NH2)(CH2)NH3]2[{Na(H2O)} ⊂ {V4HO4F2(O3PCH2PO3)4}]·7H2O (2·7H2O). The vanadium-oxyfluoride cationic unit {V4O4F2(O3PCH2PO3)4}10 − of the compounds consists of pairs of fluoride bridged {VFO5} octahedra linked through η4-diphosphonate ligands into a three polyhedra thick band. The {Na(H2O)n}+ groups occupy the interior of the band but are displaced from the centroid toward one face so as to project the aqua ligands into the extra-annular domain. The fluoride ligands bridge two vanadium sites as well as coordinating to the sodium cation.

Methylenediphosphonotetrathioate: Synthesis, Characterization, and Chemical Properties

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.

Structural Diversity of Lanthanum–Organic Frameworks Based on 1,4-Phenylenebis(methylene)diphosphonic Acid

The preparation of five different compounds, [La2(H2pmd)3(H2O)12] (1: 1D), [La2(H2pmd)(pmd)(H2O)2] (2: 3D), [La(H3pmd)(H2pmd)(H2O)] (3: 3D), [La2(H2pmd)3(H2O)2] (4: 3D), and [La2(H2pmd)(pmd)(H2O)4] (5: 3D), as crystalline materials from the reaction of 1,4-phenylenebis(methylene)diphosphonic acid (H4pmd) with lanthanum chloride is reported. Two different, fast, and economically viable synthetic approaches were employed with their various parameters being probed and, when possible, optimized to increase yields and purity: microwave-assisted synthesis (MWAS, in ca. 1 min) and a bench procedure using standard ambient conditions (one-pot, ca. 10 min). Compounds 1 and 2 were isolated as phase-pure crystalline materials. Compounds 3 and 4 were characterized by single-crystal X-ray diffraction from mixtures, and compound 5 was identified by powder X-ray diffraction studies (also from a physical mixture with 2). Structural details for all compounds were investigated by using in tandem X-ray diffraction (single-cr...

Signs of antimetastatic activity of palladium complexes of methylenediphosphonic acid in IR spectra

We have used Fourier transform IR spectroscopy methods to study normal mouse lung tissue and also after subcutaneous transplantation of a B-16 melanoma tumor in the tissue. We also studied tissues with B-16 melanoma after they were treated with coordination compounds based on palladium complexes of methylenediphosphonic acid. The IR spectra of the lung tissues with metastases in the region of the C = O stretching vibrations are different from the IR spectra of normal tissue. We identified spectroscopic signs of the presence of metastases in the lung. We show that when a cancerous tumor is treated with a preparation of palladium complexes of methylenediphosphonic acid, the spectroscopic signs of the presence of metastases in the lung are missing. After treatment with the optimal dose of this drug, the IR spectrum of the lung tissue in which multiple metastases were present before treatment corresponds to the spectrum of normal tissue. We have determined the efficacy of the antitumor activity of coordination compounds based on palladium complexes of methylenediphosphonic acid.

A novel 99mTc-labeled dimethyl-substituted zoledronic acid (DMIDP) with improved bone imaging efficiency

Abstract A novel zoledronic acid (ZL) derivative, 1-hydroxy-2-(2,4-dimethyl-1H-imidazol-1-yl)-ethane-1,1-diyldiphosphonic acid (DMIDP, dimezoledronate), was successfully prepared and labeled with 99mTc in a high labeling yield. The biodistribution in mice shows that 99mTc-DMIDP has significant advantage regarding bone resorption and clearance from soft tissues compared with 99mTc-ZL and the clinically widely-used bone-imaging agent 99mTc-MDP (methylenediphosphonic acid). Kinetics of blood clearance displayed that distribution half-life (T 1/2α ) and elimination half-life (T 1/2β ) of 99mTc-DMIDP were 2.53 min and 23.53 min, while those of 99mTc-ZL were 2.28 and 52.63 min, respectively. Excellent images of the rabbit skeleton can be quickly obtained from 99mTc-DMIDP, which was faster than 99mTc-ZL and 99mTc-MDP. The present findings indicate that 99mTc-DMIDP possesses excellent potential for application as a novel bone scanning agent.