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.     

Ion-exchange liquid chromatographic analysis of bisphosphonates by on-line post-column photochemical reaction and spectrophotometric detection

A simple ion-exchange high-performance liquid chromatographic method was developed and employed for the analysis of bisphosphonate compounds in dosage formulations using on-line post-column photochemical reactions. The method used molybdate as the post-column reagent to react with the photolyzed bisphosphonate to form phosphomolybdate for enhanced spectrophotometric detection. A bisphosphonate compound, 2-thioethane-1,1-bisphophonic acid, was selected to evaluate the separation using both isocratic and gradient elution methods, along with the effects of other experimental parameters including mobile phase composition, flow-rate and post-column reagent concentration. The gradient elution method showed improved resolution and detection sensitivity compared to the isocratic elution method. The optimized gradient method was simple, reproducible, and specific to bisphosphonate compounds. It was successfully employed for the stability study of the bisphosphonate compound in pharmaceutical dosage formulations.     

Combined Phosphoramidite‐Phosphodiester Reagents for the Synthesis of Methylene Bisphosphonates

A new class of phosphanylmethylphosphonate reagents has been developed to enable the controlled synthesis of methylene bisphosphonate mono‐ and diesters. Condensation of such reagents with an alcohol of choice through azole‐mediated phosphoramidite chemistry followed by in situ oxidation provides orthogonally protected methylene bisphosphonate tetraesters. Global deprotection of the tetraester leads to terminal methylene bisphosphonates. Alternatively, selective deprotection at the terminal phosphonate followed by a condensation between the acquired methylene bisphosphonate triester and a second alcohol leads to methylene bisphosphonates diesters.     

Adsorption-Desorption Properties of Bisphosphonates

Abstract

Aminobisphosphonates have generated substantial interest recently for the treatment of bone diseases and as plant growth regulators, both alone and as a carrier for other drugs, because of the high affinity to the hydroxyapatite (HAP). We are investigating the drug delivery action of bisphosphonates for the treatment of osteoporosis and other bone diseases. Current studies include analysis of the adsorption-desorption processes of bisphosphonate drug carriers to bone mineral, as well as the design and synthesis of new bisphosphonate derivatives. The HAP adsorption data of aminomethylenebis-phosphonate (M P) (1). alendronate (2), and the prostaglandin derivative of bisphosphonate (PGE,-BP) (3) is shown on the graph.     

Novel synthesis of bis(phosphonic acid)-steroid conjugates

An efficient synthesis has been realized for several members of a new class of potential bone resorption inhibitors consisting of steroidal oestrogenic units linked at the 3 and 17 positions to a geminal bisphosphonate moiety through an ester linkage of variable length. The convergent synthesis utilizes benzyl bisphosphonates, transesterification, and Meldrum's acid chemistry and has the potential to allow many oestrogenic derivatives as well as other biologically active compounds to be coupled to the geminal bisphosphonate moeity.     

Confinement and controlled release of bisphosphonates on ordered mesoporous silica-based materials

Bisphosphonates have been confined in siliceous ordered mesoporous materials, and the drug release rate of these systems has been investigated. The bisphosphonate adsorption rate has been increased from 1% in oral administration to around 40% locally delivered. Drug dosage can be modulated through amine modification of the material surface, leading to a bisphosphonate adsorption in the ordered mesoporous matrices 3 times larger than that for unmodified materials. The use of these drug delivery systems opens new fields with new possibilities for tissue engineering.     

Symmetrical and Unsymmetrical Bishophonate Esters Chemistry: Synthesis,Selective Hydrolysis,Isomerization

Abstract

Over thc past few years, bisphosphonatcs have bcen receiving increased auention as a new class of pharmacologically active compound. As a continuation of our research program (1,2,3) in connection with the synthesis of bisphosphonate esw I. we present here some results about thc synthesis of symmetrical and unsymmcuical bisphosphonate esms. These compounds were selectively hydrolizcd to give the following mono, di, d and tcua acids II.     

Anion-exchange separation and determination of bisphosphonates and related analytes by post-column indirect fluorescence detection

Bisphosphonic acids and their salts can be detected after their liquid chromatographic separation by post-column indirect fluorescence detection (IFD). After separation the analyte is combined with the highly fluorescent Al³⁺–morin (2′,3,4′,5,7-pentahydroxyflavone) solution and fluorescence decreases because of the formation of the nonfluorescent Al³⁺–bisphosphonate complex. The decrease in fluorescence is proportional to the amount of bisphosphonate present. Separation of the multivalent anionic bisphosphonate analytes from other anions and sample matrix is achieved on a strong base anion-exchange column with a strong, basic eluent. The post-column reaction variables, which influence IFD, are identified and optimized for the detection of the bisphosphonates after separation on the anion exchanger. The method is selective, since only a few anions will undergo a reaction with the Al³⁺–morin solution, and sensitive, detection limit for difluoromethylene bisphosphonate, F₂MDP, is 4 ng for S/N=3. The separation–IFD method can be applied to the determination of bisphosphonates, such as F₂MDP, ethane-1-hydroxy-1,1-bisphosphonic acid, dichloromethylene bisphosphonic acid, 4-amino-1-hydroxybutane-1,1-bisphosphonic acid, in biological samples. The separation–IFD method is also applicable to the detection of inositol phosphate anions.     

Synthesis of tetraethyl (2-benzyl-3-oxoisoindolyl-1,1-diyl)-bisphosphonate and its properties

The reaction of o-phthalyl chloride with sodium diethylphosphite affords a cyclic bisphosphonate, 3,3-bis(diethylphosphono)-1(3H)-isobenzofuranone. The reaction of 1(3H)-isobenzofuranone with potassium carbonate proceeds through the ring opening and elimination of one phosphonate group to give acyclic α-ketophosphonate. At the same time, the reaction of bisphosphonate with the concentrated hydrochloric acid does not lead to the ring opening but gives bisphosphonic acid in a good yield. 3,3-Bis(diethylphosphono)-1(3H)-isobenzofuranone reacts with benzylamine in the presence of triethylamine with the replacement of endocyclic oxygen atom by benzylamino group, which leads to the formation of the corresponding bisphosphonate phthalimide, the first representative of a new type of bisphosphonates and phosphorus heterocycles.     

Copper-mediated displacements of allylic THP ethers on a bisphosphonate template

The copper-mediated displacement of allylic THP ethers by Grignard reagents has been examined in a system that contains a geminal bisphosphonate ester. With Grignard reagents derived from several aromatic halides or benzyl bromide the displacement proceeds in attractive yields, but more mixed results were obtained from reactions with alkyl halides. In addition to its role as a nucleophile, the Grignard reagent also appears to deprotonate the bisphosphonate to generate an anionic intermediate. Formation of this anion appears to limit competitive nucleophilic attack at the phosphonate group and provides an intermediate that can be trapped by reaction with an electrophilic reagent such as methyl iodide to access a more substituted system.     

Elastomeric polyurethanes modified with geminal bisphosphonate groups

Three types of elastomeric segmented polyurethanes represented by a polyether‐urethane, a polyurethane‐urea, and a polycarbonate‐urethane were introduced into a modified low‐temperature variant of base‐induced N‐alkylation of urethane hard segments with an excess of 1,6‐dibromohexane in N,N′‐dimethylacetamide (DMAc), resulting in the modification of polymers with 0.08–0.26 mmol/g of pendant 6‐bromohexyl groups. Either lithium diisopropylamide (LDA) or sodium hydride was used to initiate the reaction, although LDA was found to be more suitable for the bromoalkylation. Selected bromoalkylated polyurethanes of all three types were reacted with thiol‐containing bisphosphonates, to yield the polymers modified with 0.08–0.12 mmol/g of geminal nonesterified covalently attached bisphosphonate groups. Two thiol‐containing geminal bisphosphonates used in the modifications were prepared via reactions of nucleophilic addition to vinylidene‐bisphosphonic acid. All three types of polyurethanes were found equally suitable for the modifications. The bisphosphonate‐modified polyurethanes with nonmetallic cations on the bisphosphonate groups remain soluble in the solvents suitable for the dissolution of nonmodified polymers and can be processed into films by solvent casting. After the exchange of nonmetallic cations to sodium, the polymers become insoluble in any solvent, probably as a result of the intermolecular coordination of bisphosphonate groups with the metal cations. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 105–116, 2001     

Dialkyl bisphosphonate platinum(II) complex as a potential drug for metastatic bone tumor

Bisphosphonates have high affinity for hydroxyapatite (HA), which is abundantly present in bone. Also, platinum complexes are known that have a wide spectrum of antitumor activities. The conjugate of bisphosphonate and a platinum complex might have HA affinity and antitumor activity, and become a drug for metastatic bone tumor. In this study, the authors synthesized platinum complexes that had dialkyl bisphosphonic acid as a ligand, and evaluated the possibility of the synthesized complexes as a drug for metastatic bone tumor. The synthesized dialkyl bisphosphonate platinum(II) complex was characterized, and its stability in an aqueous solution was also confirmed. The synthesized platinum complex showed higher HA affinity than other platinum complexes such as cisplatin and carboplatin in an experiment of adsorption to HA. In vitro, the platinum complex showed tumor growth inhibitory effect stronger than or equal to cisplatin, which is the most commonly used antitumor agent. Moreover, the platinum complex showed a bone absorption inhibitory effect on the osteoclast. These results suggest potential of dialkyl bisphosphonate platinum(II) complexes as a drug for metastatic bone tumor.     

A Simple and Efficient Procedure for the Synthesis of an Alendronate-Oligonucleotide Conjugate Via a Carbamate Linker

Abstract

Alendronate. an munobisphosphonate used clinically for thc treatment of osteoporosis and others bones deseases is a synthetic analog of pyrophosphate in which the labiie phosphoanhydride bond (HO)₂P(O)-O-P(O)(OH)₂ is replaced by a stable hydroxymethylene group (HO), P(O)-C(OH)R-P(O)(OH). The most important action of this bisphosphonate is the inhibition of the bone resorption. The mechanism of action is not completely elucided. One hypothesis is hat thc bisphosphonate act by suppressing osteoclast activity.[1] are used for the enzyme inhibition or for the antisens strategy parriculary in oncology The pharmacological interest of these two moieties encouraged us to bind a bisphosphonate at the 5′ OH of an oligonucleotide via a carbarnate bond. In the first time he synthesis conditions have been studied on model alcohol.     

Synthesis of New Tetraethyl(N-alkyl-1-aminoethan-1,1-diyl)bisphosphona-tes and ESR Analysis of Chemical Exchange of Derived Nitroxides of Acyclic Aminobisphosphonates

The synthesis and the full characterization of two new linear bisphosphonates (tetraethyl(N-tert-butyl-1-aminoethan-1,1-diyl)bisphosphonate and tetraethyl(N-sec-butyl-1-aminoethan-1,1-diyl)bisphosphonate), and the first analysis of the ESR spectra of the corresponding nitroxides is reported. The preliminary results of theoretical calculations on model compounds suggest a small B₀ (in the McConnell equation). The results of bisphosphonate ester and bisphosphonic acid are similar. The discrepancies of P coupling for the diphosphorus compound stems from B₂ that is different when the dihedral angle is larger than 90°.     

Synthesis and photopolymerizations of first monomers with phosphonate and bisphosphonate or phosphonic and bisphosphonic acid functionalities for potential dental applications

The first monomers containing both phosphonate and bisphosphonate (M1) or phosphonic and bisphosphonic acid (M2) functionalities are synthesized, aiming to improve binding abilities of self-etching adhesive systems and composites: An amine having both phosphonate and bisphosphonate functionalities is prepared via Michael addition reaction between diethyl (6-aminohexyl)phosphonate and tetraethyl vinylidene bisphosphonate, its reaction with 2-isocyanatoethyl methacrylate gives M1 which is converted to M2 by selective dealkylation of the phosphonate/bisphosphonate ester groups. Their copolymerization with commercial dental monomers (bisphenol A glycidyl methacrylate, triethylene glycol dimethacrylate, and 2-hydroxyethyl methacrylate) investigated by photo-differential scanning calorimetry shows adequate photopolymerization rate and conversion. X-ray diffraction, Fourier transform infrared, and X-ray photoelectron spectroscopy analyses of M2-treated hydroxyapatite particles show formation of stable M2-calcium salts. These monomers are assessed to be not toxic according to MTT standards by in vitro cytotoxicity studies with NIH 3T3, U2OS, and Saos-2 cells. All these properties make these monomers potential candidates as biocompatible components for dental adhesives and composites. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 2739–2751     

NMR studies of the bishydroxy bisphosphonate synthesis from o‐phthalic aldehyde and diethyl phosphite

The reaction of the o‐phthalic aldehyde with diethyl phosphite leading to the bishydroxy bisphosphonate has been studied. It was found that the reaction is complex and a cyclic acetal formed from the monohydroxyphosphonate is the first relatively stable product. It slowly transforms to the bishydroxy bisphosphonate. The latter compound undergoes intramolecular nucleophilic substitution of the phosphorus atom by the hydroxy group which results in a cyclic structure, a phosphonate‐hydroxyphosphate compound. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:157–164, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10014     

Synthesis of New Azole Phosphonate Precursors for Fuel Cells Proton Exchange Membranes

Herein we present the synthesis and characterization of new phosphonate‐, bisphosphonate‐ and hydroxybisphosphonatebenzimidazole derivatives substituted at the N‐1 position and new regioisomers phosphonate‐, bisphosphonate‐, and hydroxybisphosphonatebenzotriazole derivatives substituted at N‐1 or N‐2 positions. The compounds were characterized by NMR and IR spectroscopies, and mass spectrometry (low and high resolution) allowing the assignment of their structure, including the identification of regioisomers. These new azole monomers will be precursors for a mesoporous silica host to produce novel membrane materials with high proton conductivity for intermediate temperature proton exchange membrane fuel cells.     

Electrospray ionization mass spectrometry and tandem mass spectrometry of clodronate and related bisphosphonate and phosphonate compounds

The bisphosphonate family with a P-C-P structure is a broad class of drugs, widely investigated as potential inhibitors in bone diseases and calcium metabolic disorders. In this study, the mass spectrometric (MS) behavior and fragmentation of clodronate and related bisphosphonate and phosphonate compounds was studied by using negative ion electrospray ionization (ESI) with triple quadrupole and ion trap instruments. The effect of pH on the degree of deprotonation of the polyprotic bisphosphonic and phosphonic acids in negative ion ESI-MS was investigated, and the degree of deprotonation in the ESI mass spectra and the dissociation in the liquid phase were compared. The results provide evidence that the measured ESI mass spectra do not correlate with the chemistry in the liquid phase owing to the decrease in the pH of the solvent droplets during the ion evaporation process and the charge state neutralization in the gas phase. Ion trap MS(n) provided useful information on the fragmentation study of clodronate and related bisphosphonate and phosphonate compounds, in which interesting fragmentation pathways including the direct elimination of carbon monoxide from deprotonated bisphosphonates and formation of a P-P bond were observed. Reactions between the product ions with a -PO(2) group and residual water in the ion trap or in the high-pressure region of the triple quadrupole instrument formed other unexpected fragmentation paths for all the bisphosphonates studied.     

Synthesis of cycloalkenyl geminal bisphosphonates by ring closing metathesis

Five‐ and six‐membered cycloalkenyl bisphosphonates were obtained by ring closing metathesis (RCM) reactions of diethyl bis(alkenyl)methylene bisphosphonates using ruthenium alkylidene catalysts. The substitution pattern on the double bonds involved in the reaction greatly influences the reaction rate. The synthesis of the starting materials was carried out by dialkylation of tetraethyl methylene bisphosphonate or through a Michael addition of Grignard reagents to tetraethyl vinylidene bisphosphonate followed by alkylation, depending on the structure of the required substrate. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:332–338, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20622     

Structures of bisphosphonate metal complexes: zinc and cadmium complexes of clodronate and its partial ester derivatives

Four new zinc and cadmium bisphosphonates [{NaZn(Cl2CP2O6H)(H2O)5}]n (1), [{Cd2(Cl2CP2O6)(H2O)4}.H2O]n (2), [{Zn(Cl2CP2O6Pri2)(H2O)3}.H2O]n (3), and [{Cd2(Cl2CP2O6Pri2)2(MeOH)2(H2O)2}.H2O]2 (4) have been prepared and their crystal structures determined by single-crystal X-ray diffractometry. Two bisphosphonate ligands were used: clodronate, (dichloromethylene)bis(phosphonate) and its symmetrical P,P'-diisopropyl ester derivative. The structure of the Zn complex 1 is three-dimensional, consisting of one-dimensional Zn-clodronate chains connected to the three-dimensional network by Na+ ions. The structure of Cd complex 2 consists of double layers, and a unique bond was found between the Cd2+ cation and a Cl atom of clodronate. Zn complex 3 consists of one-dimensional chains, but the binding of the bisphosphonate ligands is unique: in 3 the bisphosphonate ligand is only bidentate. Compound 4 is a tetramer, and hydrogen bonds hold the tetramers together, forming a layered structure.