Iron,copper and zinc ammonium-1-hydroxyalkylidene-diphosphonates with zero-, one- and two-dimensional covalent metal–ligand structures extended into three-dimensional supramolecular networks by charge-assisted hydrogen-bonding

Hydrothermal synthesis with MCl₂ (M = Fe, Cu, and Zn) and disodium 5-ammonium-1-hydroxypentylidene-1,1-bisphosphonate, (Na⁺)₂[⁺H₃N(CH₂)₄C(OH)(PO₃²⁻)(PO₃H⁻)] (Na₂HAC₅OHP₂) or sodium 3-ammonium-1-hydroxypropylidene-1,1-bisphosphonate hydrate, Na⁺[⁺H₃N(CH₂)₂C(OH)(PO₃H^–)(PO₃H^–)]·H₂O (NaH₂PAM·H₂O) the sodium salt of pamidronic acid, H₃PAM) yielded the one-dimensional (1D) iron, molecular copper and two-dimensional (2D) zinc compounds 1D-{[Fe(μ₃-η⁵-HAC₅OHP₂)]·H₂O}, 1, [Cu(η²-H₂AC₅OHP₂)₂], 2, 2D-{[Zn₂(μ₅-η⁷-AC₅OHP₂)Cl], 3, and 2D-{[Zn(μ₂-η³-H₂PAM)₂], 4, respectively. The bisphosphonate ligand bridges (μ_n) between 2–5 metal atoms and uses 2–7 oxygen donor atoms towards metal coordination (ηⁿ). The zwitterionic nature of the now bis- or tetrakis-deprotonated ammonium–bisphosphonate is retained in the metal complexes. From the reaction of NiCl₂ and Na₂HAC₅OHP₂ the zwitterionic 5-ammonium-1-hydroxypentylidene-1-phosphonic acid, ⁺H₃N(CH₂)₄CH(OH)PO₃H⁻, 5 was obtained as a product of the ligand P–C bond hydrolysis. Adjacent strands, molecules or layers in 1–4, respectively are organized through the Coulomb attraction between the positive ammonium group and the negative phosphonate groups, supported by hydrogen-bonding. Each protic H atom on the C–OH, NH₃⁺ and –PO₃H⁻ group is involved in charge-assisted hydrogen-bonding. The ammonium-pentylidene groups act as hydrophobic separators between the hydrophilic units with the polar M{C(OH)(PO₃)₂} and {NH₃} units. Bond valence sum calculations support the Fe(II) oxidation state in 1, which was experimentally determined from a quantitative polarographic Fe(II)/Fe(III) speciation analysis as well as a temperature variable magnetic study.     

Synthesis of dendritic bisphosphonates as bone targeting ligands

A dendritic bisphosphonate carrying three bisphosphonate (BP) units in close proximity was designed as a ligand to conjugate large therapeutic molecules for their bone selective delivery. The Bu₃P-catalyzed conjugate addition of nitromethane to vinylidene bisphosphonate was effective to construct a quaternary carbon center carrying BP units. Owing to multivalent interactions, the dendritic bisphosphonate showed considerable affinity for the bone mineral hydroxyapatite even in the presence of a competitor, demonstrating potential as a bone targeting ligand.     

双膦酸化合物对基质金属蛋白酶的抑制效应及机理

根据基质金属蛋白酶(MMPs)的活性位点附近三维空间结构, 设计合成了4种双膦酸类化合物, 利用酶促反应动力学方法对比测试了双膦酸化合物及阿伦磷酸钠(Alendronate)对MMPs的抑制效果; 结合分子对接方法以及荧光滴定光谱研究了双膦酸化合物与MMPs的分子识别和作用机理, 并得到了二者的结合模型.     

Rh(III)-catalyzed, 1,2,3-triazole-assisted directed CH coupling with diazo diphosphonates

A mild and efficient procedure was developed for the [Cp1Rh(III)]-catalyzed, 1,2,3-triazole directed CH coupling with diazomethylene-diphosphonates. This protocol provided a step- and atom-economical protocol for CC bond formation and led to structurally diverse 2-(1,2,3-triazol-2-yl)benzyl diphosphonates in good to excellent yields.     

Bisphosphonate prodrugs: synthesis of new aromatic and aliphatic 1-hydroxy-1,1-bisphosphonate partial esters

Methods for the preparation of various 1-hydroxy-1,1-bisphosphonate partial esters were developed. They were obtained from (alkyl or phenyl) bis(trimethylsilyl) phosphite and aromatic or aliphatic acid chlorides, followed by methanolysis.     

解热镇痛药——双膦酸酯化合物的合成

利用具有趋骨性和抗炎镇痛活性的双膦酸化合物与治疗风湿性关节炎的解热镇痛药的加和作用，设计并合成了５个解热镇痛药－－双膦酸酯偶联物，希望得到骨靶向性的治疗骨关节炎的先导物。     

The Synthesis and Evaluation of Quaternary Pyridinium Bisphosphonates as Potent Anti-Resorptives

Abstract

Several novel quaternary pyridinium bisphosphonates have been synthesised and their efficacy as potential anti-resorptive bone agents have been tested in Dictyostelium discoideum. This assay has been shown to accurately reflect the potency of a bisphosphonic acid as an anti-resorptive compound. All the quaternary bisphosphonates are very potent growth inhibitors but results indicate that the more potent compounds are those containing hydrophobic, bulky groups.     

One-pot synthesis of 1-hydroxymethylene-1,1-bisphosphonate partial esters

A selective one-pot procedure of synthesis of 1-hydroxymethylene-1,1-bisphosphonic partial trimethylesters and P,P-, P,P′-diesters was described.     

An Efficient Synthesis of Aromatic 1-Hydroxymethylene-1,1-bisphosphonates from Aldehydes

A simple and efficient procedure for synthesis of 1-hydroxymethylene-1,1-bisphosphoates from aldchydes is described.This method was applied to the synthesis of novel catechol substituted bisphosphonates as the anti-osteoporosis agents.     

Molecular interactions of nitrogen-containing bisphosphonates within farnesyl diphosphate synthase

Bisphosphonates, known for their effectiveness in the treatment of osteoporosis, inhibit bone resorption via mechanisms that involve binding to bone mineral and cellular effects on osteoclasts. The major molecular target of nitrogen-containing bisphosphonates (N-BPs) in osteoclasts is farnesyl diphosphate synthase (FPPS). N-BPs likely inhibit this enzyme by mimicking one or more of the natural isoprenoid lipid substrates (GPP/DMAPP and IPP) but the mode of inhibition is not established. The active site of FPPS comprises a subsite for each substrate. Kinetic studies with recombinant human FPPS indicate that both potent (risedronate) and weak (NE-58051) enzyme inhibitors compete with GPP for binding to FPPS, however, binding to this site does not completely explain the difference in potency of the two inhibitors, suggesting that a second binding site may also be a target of bisphosphonate inhibition. Using the docking software suite Autodock, we explored a dual inhibitor binding mode for recombinant human FPPS. Experimental support for dual binding is suggested by Dixon plots for the inhibitors. N-BPs may inhibit by binding to both the GPP and a second site with differences in potency at least partly arising from inhibition at the second site.