- Bisphosphonates derived from fatty acids are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase
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Studies on the mode of action of a series of bisphosphonates derived from fatty acids, which had previously proved to be potent inhibitors against Trypanosoma cruzi proliferation in in vitro assays, have been performed. Some of these drugs proved to be potent inhibitors against the intracellular form of the parasite, exhibiting IC50 values at the low micromolar level. As bisphosphonates are FDA clinically approved for treatment of bone resorption disorders, their potential innocuousness makes them good candidates to control tropical diseases.
- Szajnman, Sergio H.,Montalvetti, Andrea,Wang, Youhong,Docampo, Roberto,Rodriguez, Juan B.
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Read Online
- On the acidity of substituted methylenediphosphonates and their interaction with alkali metal ions
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The acidity of and Li+, Na+, K+, and Cs+ complexing with a series of substituted methylenediphosphonates have been determined at 25° in 0.5 M tetramethylammonium chloride. The acid properties of the alkyl-substituted methylenediphosphonates have been shown to be correlated with the electron-donor ability of the substituents attached to the bridging carbon atom. Also, logβMHiL (i = 0, 1) is predicted by an equation involving the reciprocal of the radius of the bare cation and the sum of the Taft σ* values. For 1-hydroxyethylidene-1,1-diphosphonic acid evidence is presented for intramolecular binding of the protons and the metal ions by the hydroxyl group.
- Carroll, Robert L.,Irani, Riyad R.
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Read Online
- Challenging synthesis of bisphosphonate derivatives with reduced steric hindrance
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An alternative approach is reported for the synthesis of methyl ester protected bisphosphonate building blocks, such as methylene bisphosphonate, vinylidenebisphosphonate and aryl substituted prochiral vinylidenebisphosphonates, that cannot be obtained directly from dimethyl phosphite and dichloromethane.
- Chiminazzo, Andrea,Sperni, Laura,Fabris, Fabrizio,Scarso, Alessandro
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supporting information
(2021/04/12)
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- Modification of Amorphous Mesoporous Zirconia Nanoparticles with Bisphosphonic Acids: A Straightforward Approach for Tailoring the Surface Properties of the Nanoparticles
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The use of readily prepared bisphosphonic acids obtained in few steps through a thio-Michael addition of commercially available thiols on tetraethyl vinylidenebisphosphonate enables the straightforward surface modification of amorphous mesoporous zirconia nanoparticles. Simple stirring of the zirconia nanoparticles in a buffered aqueous solution of the proper bisphosphonic acid leads to the surface functionalization of the nanoparticles with different kinds of functional groups, charge and hydrophobic properties. Formation of both chemisorbed and physisorbed layers of the bisphosphonic acid take place, observing after extensive washing a grafting density of 1.1 molecules/nm2 with negligible release in neutral or acidic pH conditions, demonstrating stronger loading compared to monophosphonate derivatives. The modified nanoparticles were characterized by IR, XPS, ζ-potential analysis to investigate the loading of the bisphosphonic acid, FE-SEM to investigate the size and morphologies of the nanoparticles and 31P and 1H MAS NMR to investigate the coordination motif of the phosphonate units on the surface. All these analytical techniques demonstrated the strong affinity of the bisphosphonic moiety for the Zr(IV) metal centers. The functionalization with bisphosphonic acids represents a straightforward covalent approach for tailoring the superficial properties of zirconia nanoparticles, much straightforward compared the classic use of trisalkoxysilane or trichlorosilane reagents typically employed for the functionalization of silica and metal oxide nanoparticles. Extension of the use of bisphosphonates to other metal oxide nanoparticles is advisable.
- Hossain, Khohinur,Florean, Luca,Del Tedesco, Anna,Cattaruzza, Elti,Geppi, Marco,Borsacchi, Silvia,Canton, Patrizia,Benedetti, Alvise,Riello, Pietro,Scarso, Alessandro
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supporting information
p. 17941 - 17951
(2021/11/20)
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- Diketopyrrolopyrrole Bis-Phosphonate Conjugate: A New Fluorescent Probe for In Vitro Bone Imaging
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The synthesis of a conjugate molecule between an unusual red-fluorescent diketopyrrolopyrrole (DPP) unit and a bis-phosphonate (BP) precursor by a click-chemistry strategy to target bone tissue and monitor the interaction is reported. After thorough investigation, conjugation through a triazole unit between a γ-azido rather than a β-azido BP and an alkyne-functionalized DPP fluorophore group turned out to be the winning strategy. Visualization of the DPP-BP conjugate on osteoclasts and specific antiresorption activity were successfully demonstrated.
- Chiminazzo, Andrea,Borsato, Giuseppe,Favero, Alessia,Fabbro, Chiara,McKenna, Charles E.,Dalle Carbonare, Luca Giuseppe,Valenti, Maria Teresa,Fabris, Fabrizio,Scarso, Alessandro
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supporting information
p. 3617 - 3626
(2019/02/19)
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- Transition state in DNA polymerase β Catalysis: Rate-Limiting chemistry altered by base-pair configuration
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Kinetics studies of dNTP analogues having pyrophosphate-mimicking β,β-pCXYp leaving groups with variable X and Y substitution reveal striking differences in the chemical transition-state energy for DNA polymerase β that depend on all aspects of base-pairing configurations, including whether the incoming dNTP is a purine or pyrimidine and if base-pairings are right (T*A and G*C) or wrong (T*G and G*T). Br?nsted plots of the catalytic rate constant (log(kpol)) versus pKa4 for the leaving group exhibit linear free energy relationships (LFERs) with negative slopes ranging from -0.6 to -2.0, consistent with chemical rate-determining transition-states in which the active-site adjusts to charge-stabilization demand during chemistry depending on base-pair configuration. The Br?nsted slopes as well as the intercepts differ dramatically and provide the first direct evidence that dNTP base recognition by the enzyme-primer-template complex triggers a conformational change in the catalytic region of the active-site that significantly modifies the rate-determining chemical step.
- Oertell, Keriann,Chamberlain, Brian T.,Wu, Yue,Ferri, Elena,Kashemirov, Boris A.,Beard, William A.,Wilson, Samuel H.,McKenna, Charles E.,Goodman, Myron F.
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p. 1842 - 1848
(2014/04/17)
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- The effect of bisphosphonate acidity on the activity of a thymidylyltransferase
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Thymidylyltransferases (thymidine diphospho pyrophosphorylases) are nucleotidylyltransferases that play key roles in the biosynthesis of carbohydrate components within bacterial cell walls and in the biosynthesis of glycosylated natural products. They catalyze the formation of sugar nucleotides concomitant with the release of pyrophosphate. Protein engineering of thymidylyltransferases has been an approach for the production of a variety of non-physiological sugar nucleotides. In this work, we have explored chemical approaches towards modifying the activity of the thymidylyltransferase (Cps2L) cloned from S. pneumoniae, through the use of chemically synthesized 'activated' nucleoside triphosphates with enhanced leaving groups, or by switching the metal ion co-factor specificity. Within a series of phosphonate-containing nucleoside triphosphate analogues, thymidylyltransferase activity is enhanced based on the acidity of the leaving group and a Br?nsted-type analysis indicated that leaving group departure is rate limiting. We have also determined IC50 values for a series of bisphosphonates as inhibitors of thymidylyltransferases. No correlation between the acidity of the inhibitors (pKa) and the magnitude of enzyme inhibition was found. The Royal Society of Chemistry.
- Beaton, Stephen A.,Jiang, Patricia M.,Melong, Jonathan C.,Loranger, Matthew W.,Mohamady, Samy,Veinot, Thomas I.,Jakeman, David L.
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supporting information
p. 5473 - 5480
(2013/09/02)
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- Biphenyl Sulfonylamino Methyl Bisphosphonic Acids as Inhibitors of Matrix Metalloproteinases and Bone Resorption
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A number of matrix metalloproteinases (MMPs), proteins important in the balance of bone remodeling, play a critical role both in cancer metastasis and in bone matrix turnover associated with the presence of cancer cells in bone. Here, we report the synthesis and biological evaluation of a new class of MMP inhibitors characterized by a bisphosphonate function as the zinc binding group. Since the bisphosphonate group is also implicated in osteoclast inhibition and provides a preferential affinity to biological apatite, the new molecules can be regarded as bone-seeking medicinal agents. Docking experiments were performed to clarify the mode of binding of bisphosphonate inhibitors in the active site of MMP-2. The most promising of the studied bisphosphonates showed nanomolar inhibition against MMP-2 and resulted in potent inhibition of osteoclastic bone resorption in vitro. Bone resorption inhibition: A series of biphenyl sulfonylamino methyl bisphosphonic acids were synthesized and tested both as matrix metalloproteinase (MMP) and bone resorption inhibitors. The most promising compound (15) showed nanomolar activity against MMP-2 and good selectivity over MMP-8, -9, and -14; furthermore, it showed a very good antiresorptive activity comparable with that of zolendronic acid.
- Rubino, Maria Teresa,Agamennone, Mariangela,Campestre, Cristina,Campiglia, Pietro,Cremasco, Viviana,Faccio, Roberta,Laghezza, Antonio,Loiodice, Fulvio,Maggi, Dariana,Panza, Emilia,Rossello, Armando,Tortorella, Paolo
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experimental part
p. 1258 - 1268
(2012/05/05)
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- An improved method for the synthesis of nucleoside triphosphate analogues
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Nucleoside monophosphates, when activated by trifluoroacetic anhydride and N-methylimidazole, efficiently couple with a variety of electron-deficient diphosphonates in a reproducible and efficient manner (72% isolated yield). Unlike traditional methods for the preparation of nucleoside 5′-β,γ-methylenetriphosphate analogues, there is no requirement for predrying, or conversion to specific salt forms, of commercially available nucleoside monophosphate starting materials.
- Mohamady, Samy,Jakeman, David L.
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p. 10588 - 10591
(2007/10/03)
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- Bisphosphonate conjugates and methods of making and using the same
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The present invention provides novel bisphosphonate conjugates, pharmaceutical compositions comprising bisphosphonate conjugates and methods of using such analogs in the treatment of bone cancer, bone-related diseases and diseases of the soft tissues surrounding bones.
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- Synthesis of new potential chelating agents: Catechol-bisphosphonate conjugates for metal intoxication therapy
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In a quest for better chelating therapy drugs for the treatment of intoxication by Fe, Al, or actinides, three new series of bisphosphonates conjugated with catechol were synthesized.
- Xu, Guangyu,Yang, Chunhao,Liu, Bo,Wu, Xihan,Xie, Yuyuan
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p. 251 - 257
(2007/10/03)
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- Facile synthesis of symmetric esters of alkylenebisphosphonic acids
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A facile synthesis of symmetric esters of C1-C10 alkylenebisphopsphonic acids is disclosed in which a C1-C10 alkylenebis(phosphonic dichloride) is reacted with an alcohol in the presence of a catalytic amount of 1H-tetrazole and a base in an aprotic solvent to form a first reaction mixture. The first reaction mixture is maintained for a time period sufficient to form a C1-C10 alkylenebis(chloro ester phosphonate) that is reacted under basic conditions with an excess of a hydroxylated compound to form a second reaction mixture that is itself maintained for a time period sufficient to form a C1-C10 alkylenebis(ester phosphonate) partial ester, homoleptic tetraester or mixed tetraester. The material so formed can be recovered or used as is.
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- Simple synthesis of oxiranylidene-2,2-bis(phosphonic acid): Tetrabenzyl geminal bisphosphonate esters as useful intermediates
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Tetrabenzyl geminal bisphosphonate esters are shown to be useful synthetic equivalents of 1,1-bis(phosphonic acid)s which may be easily functionalized at the central carbon atom without phosphonate ester hydrolysis. The parent bis(phosphonic acid) unit is readily regenerated by hydrogenolysis. The chemistry is used to prepare the elusive epoxide oxiranylidene-2,2-bis(phosphonic acid) by a short and reliable procedure.
- Bulman Page, Philip C.,McKenzie, Michael J.,Gallagher, James A.
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p. 211 - 218
(2007/10/03)
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- Bisphosphonate conjugates and methods of making and using the same
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The present invention is directed to particular bisphosphonate compounds, and in particular, to bisphosphonate conjugates that are useful in the treatment of soft tissues surrounding bone and bone-related diseases, such as bone cancer and osteoporosis.
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Two original acid derivatives of methylene diphosphonic acid (MDP) with two inequivalent phosphorus atoms have been synthesised: [(thiophosphonato)-methyl] phosphonic acid, (MDPS), and [(isopropylamido phosphonato)-methyl] phosphonic acid, (MDPN). A potentiometric study allowed to define the stoechiometry of the complex formed between MDP and magnesium (II) in alcaline medium and a 31P NMR study proved the dissymetric structure of this MDPMg2+ complex. The displacement of the coordination equilibrium between Black Eriochrome T and magnesium (II) permitted to compare the coordination strength of MDP, MDPS and MDPN with the cation Mg2+.
- Etienne,Rubini,Bessiere,Walcarius,Grison,Coutrot
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- First Use of Benzyl Phosphites in the Michaelis-Arbuzov Reaction Synthesis of Mono-, Di-, and Triphosphate Analogs
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Benzyl phosphites were used in the Michaelis-Arbuzov reaction.Special experimental conditions allowed preparation of a set of phosphonate analogs of mono-, di-, and triphosphate.Furthermore, regioselective mono-deprotection mades these molecules useful building blocks for the synthesis of analogs of polyphosphorylated compounds of biological interest (e.g. nucleotides), after removal of all phosphonate benzyl ester groups under very mild conditions and high yields.
- Saady, Mourad,Lebeau, Luc,Mioskowski, Charles
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p. 670 - 678
(2007/10/02)
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- Oral compositions
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Oral compositions providing antitartar and antigingivitis benefits containing an antitartar agent and a stannous salt.
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- Phosphonate reagent compositions
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Novel phosphonate compounds of the formula STR1 are disclosed and claimed, as well as methods for manufacturing the phosphonates from C-14 through C-16 aldehydes. The phosphonate compounds of the present invention can be employed to form 13-cis retinoic acid, retin-A and beta-carotene.
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- (Cycloalkylamino)methylenebis(phosphonic acid)
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(Cycloalkylamino)methylenebis(phosphonic acid) represented by the general formula: STR1 in which, R, R1, R2, R3 and R4 represent a hydrogen atom or a lower alkyl group, and n represents an integer from 3 to 10, a lower alkyl ester thereof or a pharmaceutically acceptable salt thereof; and a bone-resorption inhibitor and an anti-arthritis containing the same.
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- 4-nitrophenyl 4-morpholinylphosphonochloridate: a convenient reagent for the synthesis of ribonucleoside mono-, di- and tri-phosphates
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The synthesis of the crystalline and easily accessible phosphorylating agent 4-nitrophenyl 7-morpholinylphosphonochloridate is reported.Its application to the preparation of 5'-phosphorylated ribonucleosides (e.g. pA, ppA and pppA) as well as RNA fragments (e.g. pUpU and ppUpU) is demonstrated.Further, special attention is paid to the mild removal of the 4-nitrophenyl group from fully protected phosphotriester intermediates.
- Hartog, J. A. J. den,Boom, J. H. van
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p. 285 - 290
(2007/10/02)
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- Oral composition for calculus retardation
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Oral compositions, such as toothpaste, mouthwash, and the like, containing certain polyphosphonic acids and their salts which retard dental calculus formation without damaging tooth structure.
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