A grande aplicação dos radiofármacos está em medicina nuclear diagnóstica representando 95% dos procedimentos realizados, porém, nos últimos anos, tem crescido consideravelmente a sua aplicação em procedimentos terapêuticos. Os radionuclídeos que emitem particulas ionizantes (α, β e elétrons Auger) são indicados para tratamento de tumores. Tumores malignos são responsáveis por aproximadamente 12% dos óbitos e representam a terceira causa de mortalidade no Brasil. O 188Re é um dos mais atrativos radioisótopos para uma variedade de aplicações terapêuticas em medicina nuclear, oncologia e intervenções cardiológicas, é totalmente favorável e conveniente pelo fato de que ele é livre de carregador e pode ser obtido de forma econômica na forma de um gerador de 188W/188Re, além de possuir uma meia-vida fisica de 16,9 horas e 100% de emissão de radiação β-. A partir da década de 2000 vêm sendo realizadas diversas investigações envolvendo marcações de moléculas com 188Re. Os tumores metastáticos são a forma mais comum de malignidade esquelética. Em casos metastáticos os principais objetivos do tratamento são a prevenção de fraturas patológicas e promover a sobrevida com o máximo de preservação de função permitindo que o paciente mantenha o máximo possível de mobilidade e controle da dor. O objetivo deste trabalho foi realizar a comparação das marcações de diversos fosfonatos (Metileno disfofonato de Sódio MDP...
Layered materials including metal phosphates and phosphonates have been widely investigated in several fields acting as good selective catalysts in a great number of oxidative reactions. Zirconium phosphate amorphous [Zr(HPO(4))(2)center dot H(2)O; ZrPA], sodium exchanged zirconium phosphate amorphous [Zr(NaPO(4))(2); NaZrPA], potassium exchanged zirconium phosphate amorphous [Zr(KPO(4))(2); KZrPA], zirconium phenylphosphonate amorphous [Zr(O(3)PC(6)H(5))(2); ZrPPA], zirconium carboxyethylphosphonate [Zr(O(3)PCH(2)CH(2)COOH)(2); ZrCEP] and aluminium carboxyethylphosphonate [Al(3)(OH)(3)(O(3)PCH(2)CH(2)CO(2))(2)center dot 3H(2)O; AlCEP] were prepared, characterized and evaluated as selective catalysts in the Baeyer-Villiger oxidation of cyclopentanone, p-methoxybenzaldehyde and 2,4,6-trimethylbenzaldehyde by hydrogen peroxide, in acetic acid. The selectivity of delta-valerolactone, p-methoxyphenol and 2,4,6-trimethylphenol have been found to be strongly related with the properties and structure of each catalyst.
Tetravalent metal phosphates and phosphonates form highly insoluble inorganic polymers and can act as good catalysts in some oxidative reactions. In the present work, zirconium phosphate amorphous (ZrPA), scandium exchanged zirconium phosphate amorphous (ScZrPA), sodium exchanged zirconium phosphate amorphous (NaZrPA), potassium exchanged zirconium phosphate amorphous (KZrPA), zirconium phenylphosphonate amorphous (ZrPPA) and zirconium phenylphosphonate phosphate amorphous (ZrPA/ZrPPA), were prepared and evaluated as catalysts for the oxidation of 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene [(+)-3-carene)] by hydrogen peroxide, in different solvents. It was found that the oxidation reaction of (+)-3-carene yielded three major products, namely alpha-3,4-epoxycarane, carane-3 beta,4 alpha-diol and 3 beta-acetoxycaran-4 alpha-ol, depending on the catalyst and solvent conditions. No beta-3,4-epoxycarane was detected in the studied conditions. (C) 2008 Elsevier B.V. All rights reserved.
Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a, 6b, 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16. The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations (15 → 16 and 22 → 23 + 24) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a, 26b, 26c and 26d. Acid hydrolysis provided the adenine and guanine analogues 6a, 6b, 7a and 7b. Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV).
The Escherichia coli phnD gene is hypothesized to code for the periplasmic binding component of a phosphonate uptake system. Here we report the characterization of the phosphonate-binding properties of the phnD protein product. We find that PhnD exhibits high affinity for 2-aminoethylphosphonate (5 nM), the most commonly occurring natural phosphonate produced by lower eukaryotes, but also binds several other phosphonates with micromolar affinities. A significant number of man-made phosphonates, such as insecticides and chemical warfare agents, are chemical threats and environmental pollutants. Consequently, there is an interest in developing methods for the detection and bioremediation of phosphonates. Bacterial periplasmic-binding proteins have been utilized for developing reagentless biosensors that report analytes by coupling ligand-binding events to changes in the emission properties of a covalently conjugated environmentally-sensitive fluorophore. Several PhnD conjugates described here show large changes in fluorescence upon binding to methylphosphonate (MP), with two conjugates exhibiting up to 50% decrease in emission intensity. Since MP is the final degradation product of many nerve agents, these PhnD conjugates can function as components in a biosensor system for chemical warfare agents.
Modification of the implant surface with the Arg-Gly-Asp tripeptide (RGD) putatively facilitates osteoblast attachment for improved implant fixation in the laboratory. We compared the histomorphometric and mechanical performance of titanium implants coated with RGD using a novel interface of self-assembled monolayers of phosphonates (RGD/SAMP) and implants coated with RGD using the more conventional thiolate-gold interface (RGD/thiolate-gold). We hypothesized RGD/SAMP-coated implants would show greater bone ongrowth and implant fixation than RGD/thiolate-gold-coated ones. We implanted an RGD/SAMP-coated implant in one femur and an RGD/thiolate-gold-coated in the contralateral femur of 60 rats. At 2, 4, and 8 weeks after implantation, 10 rats were sacrificed for histologic evaluation and another 10 for biomechanical testing. Bone-implant ongrowth and implant force-to-failure of the two implants were similar at all times. Although RGD/SAMP-coated implants did not show superior bone ongrowth and implant fixation, RGD/SAMP-coated implants have at least equally good histomorphometric and mechanical in vivo performance as RGD/thiolate-gold-coated ones. Additional in vivo characterization of self-assembled monolayer films of phosphonates as interface to bond RGD to titanium is needed to explore its full potential and seems justified based on the results of this study.
Tertiary α-hydroxy phosphonates have been synthesized in good yields and high enantiomeric purity (up to 99% ee) through a novel L-proline-catalyzed cross aldol reaction of α-keto phosphonates and ketones.
Patients infected with human immunodeficiency virus (HIV) often suffer from herpesvirus infections as a result of immunosuppression. These infections can occur while patients are receiving antiretroviral therapy, and additional drugs required to treat their infection can adversely affect compliance. It would be useful to have antivirals with a broader spectrum of activity that included both HIV and the herpesviruses. We reported previously that alkoxyalkyl ester prodrugs of cidofovir are up to 3 orders of magnitude more active against herpesvirus replication and may be less toxic than the unmodified drug. To determine if this strategy would be effective for certain phosphonomethoxyethyl nucleoside phosphonates which are also active against HIV infections, the hexadecyloxypropyl (HDP) esters of 1-(phosphonomethoxyethyl)-cytosine, 1-(phosphonomethoxyethyl)-5-bromo-cytosine (PME-5BrC), 1-(phosphonomethoxyethyl)-5-fluoro-cytosine, 9-(phosphonomethoxyethyl)-2,6-diaminopurine (PME-DAP), and 9-(phosphonomethoxyethyl)-2-amino-6-cyclopropylaminopurine (PME-cPrDAP) were evaluated for activity against herpesvirus replication. The HDP esters were substantially more active than the unmodified acyclic nucleoside phosphonates, indicating that esterification with alkoxyalkyl groups increases the antiviral activity of many acyclic nucleoside phosphonates. The most interesting compounds included HDP-PME-cPrDAP and HDP-PME-DAP...
The conformationally locked carbocyclic nucleoside phosphonates 2 and 2′ and key intermediates for the synthesis of 3 and 3′ were prepared from a chiral cyclopentene derivative and epicholorohydrine, respectively. The structure of the nucleoside precursor 6 was confirmed by X-ray crystallography. These carbocyclic nucleoside phosphonates were designed to probe their binding interactions at the active site of HIV-1-RT.
Although the acyclic nucleoside phosphonates cidofovir, adefovir and tenofovir are approved for treating human cytomegalovirus, hepatitis B and HIV infections, respectively, their utility is limited by low oral bioavailability, renal toxicity and poor cell penetration. Research over the past decade has shown that these undesirable features can be eliminated by esterifying the compounds with an alkoxyalkyl group, in effect disguising them as lysophospholipids. In this modified form, the drugs are readily taken up in the gastrointestinal tract and have a prolonged circulation time in plasma. The active metabolite also has a long half life within cells, permitting infrequent dosing. Because these modified drugs are not recognized by the transport mechanisms that cause the accumulation of acyclic nucleoside phosphonates in renal tubular cells, they lack nephrotoxicity. Alkoxyalkyl esterification also markedly increases the in vitro antiviral activity of acyclic nucleoside phosphonates by improving their delivery into cells. For example, an alkoxyalkyl ester of cyclic-cidofovir, a less soluble compound, retains antiviral activity for 3 months following a single intravitreal injection. Two of these novel compounds, hexadecyloxypropyl-cidofovir (CMX-001) and hexadecyloxypropyl-tenofovir (CMX-157) are now in clinical development. This article focuses on the hexadecyloxypropyl and octadecyloxyethyl esters of cidofovir and (S)-HPMPA...
Cyclic nucleoside phosphonates connected through a P-O-C linkage to a promoiety represent a class of prodrugs designed to overcome the low oral bioavailability of parent antiviral acyclic nucleoside phosphonates. In our prodrug approach, a non-toxic promoiety such as an amino acid or dipeptide is conjugated to the cyclic form of the parent drug by esterification of the phosphonic acid moiety by an alcoholic amino acid side chain (Ser, Tyr, and analogues) or through a glycol linker. For the biological evaluation and investigation of the pharmacokinetic profiles of these modified nucleoside phosphonates, a reliable synthetic procedure that allows preparation of sufficient amount of potential prodrugs is needed. This unit describes a method for generating peptidomimetic conjugates of two potent antiviral acyclic nucleoside phosphonates: 1-[(2S)-3-hydroxy-2-phosphonomethoxypropyl]cytosine ((S)-HPMPC, and 9-[(2S)-3-hydroxy-2-phosphonomethoxypropyl]adenine ((S)-HPMPA). Two alternate strategies allowing synthesizing selected amino acid, dipeptide, or ethylene glycol-linked amino acid prodrugs of (S)-HPMPC and (S)-HPMPA in solution and using a solid-phase approach are presented.
The preparation of partial esters of methylenebisphosphonic acids has been of recent interest due to their potential therapeutic applications. This paper describes a convenient method to prepare symmetrical methylenebis(alkyl hydrogen phosphonates) by the selective cleavage of the corresponding methylenebis(dialkyl phosphonate) with refluxing morpholine. The effects of structural variations on the amine as well as the substrate have been investigated to understand the scope and limitations of this reaction. A superior approach to hindered bisphosphonic acid esters involves the cleavage of their dimethyl esters, 4, using morpholine. This method is also useful to access a number of C-alkyl dialkyl methylenebisphosphonic acids such as 6. This study clearly shows that cleavage with morpholine is convenient, inexpensive, and allows for the preparation of a variety of P,P’-disubstituted partial esters in good yields and high purity.
An unexpected dichotomy was observed in the Ru-catalyzed asymmetric transfer hydrogenation of acyl phosphonates: reduction proceeded from the opposite face relative to that observed in the analogous reduction of α-keto esters. The first highly selective catalytic hydrogenation of acyl phosphonates was utilized in the dynamic kinetic resolution of α-aryl acyl phosphonates providing β-stereogenic α-hydroxy phosphonic acid derivatives.
Fonte: Amer Chemical SocPublicador: Amer Chemical Soc
Tipo: Artigo de Revista Científica
Publicado em //2002Português
Relevância na Pesquisa
Addition of stabilized Horner-Wadsworth-Emmons (HWE) phosphonates to substituted 1,2-dioxines leads to diastereomerically pure di- and trisubstituted cyclopropanes in high yields and represents a viable alternative to ylides in the cyclopropanation reaction involving 1,2-dioxines. While yields are comparable, reaction times with these stabilized phosphonates were accelerated and the diastereoselectivity for this cyclopropanation reaction was significantly greater than for the previously reported examples employing ylides.
Integrating multiple functions into one host for improved catalytic performance is challenging and promising for both catalysis and material science. Herein a new acid–base bifunctional periodic mesoporous titanium phosphonate hybrid material is synthesized by a facile one-pot hydrothermal method, using alendronate sodium trihydrate as a coupling molecule. The new material possesses highly periodic mesopores with a large specific surface area of 540 m2 g–1 and pore volume of 0.43 cm3 g–1, favoring the smooth mass transport of reactants and products during the catalytic reaction. It also has an organic–inorganic hybrid framework with homogeneously incorporated phosphonate groups, in which a large number of accessible acidic P–OH and basic −NH2 sites can, respectively, activate aziridine and CO2, synergistically leading to the high conversion (>99%), yield (98%), and regioselectivity (98:2) for the CO2 cycloaddition reaction. The catalytic activity is better than that of the scarcely reported heterogeneous catalysts for aziridine and CO2 cycloaddition and even comparable to that of the state-of-the-art homogeneous ones. Moreover, being superior to the other catalysts, the metal phosphonate materials can be easily separated and reused repeatedly without activity loss...
A series of gadolinium based complexes have been designed, synthesized and characterized. Finally in vivo investigations of the compounds have been preformed by combined electrophysiological and fMRI methods.
Acyclic bifunctional chelating agents were synthesized by two different ways starting from the dimethylester of nitro- or aminoisophtalic acid.
Complexes with gadolinium and europium were obtained and relaxivities were measured at 300 MHz and 25oC. The very poor solubility of the complexes in water and most organic solvents indicate the formation of di- or polymer chains upon the complexation. This makes the complexes useless for further investigations as MRI contrast agents. Although the amino derivative can be modified and used as a building blocks in the syntheses of the specific chelators.
The second set of compounds was designed to be sensitive to changes of pH. Protected and unprotected phosphonates were used to study the effect of the charge and acidity of the complexes on the relaxivity.
Thermodynamic investigations of the ligands have been performed using glass-electrode potentiometric titrations and protonation constants of the phosphonates as well as stability constants of the ligand-calcium(II) complexes (as model for the stability of gadolinium(III) complexes) have been determined. pK values of the phosphonic functional groups increase with increase of the chain length of the pendant arm. The reverse behavior was observed for the second protonation constant of the nitrogen atom of the cyclen rim. Relaxometric measurements of the gadolinium(III) complexes have been performed at various magnetic fields (20...
In this study, several synthesis routes were adopted to prepare nanometer sized metal-phosphonate particles to expand their use in the delivery of phosphonate mineral scale inhibitors into formation porous media for oilfield scale control. An aqueous solution of calcium chloride or zinc chloride was mixed with a basic phosphonate solution to form nanometer sized particles. The physical and chemical properties of the fabricated nanomaterials and their solutions have been carefully evaluated. The obtained nanomaterial suspensions were stable for a certain period of time at 70°C in saline solutions. The nanomaterials demonstrated a good migration performance through formation porous media. Transportability was affected by both the flow velocity and the surface chemistry of the nanomaterials as well as the formation medium. The transport of these nanomaterials can be enhanced, when the formation materials were pre-flushed by surfactant solutions. The potential application of the synthesized nanomaterials for scale treatment in oilfields has been investigated by a series of laboratory squeeze simulation tests. The synthesized nanomaterials were injected into formation medium and retained on the medium surfaces. After a shut-in period, the inhibitor nanomaterials slowly released phosphonates into the produced fluid to prevent scale formation. It has been observed that the prepared nanomaterials are able to return phosphonates in a similar return profile as that of the conventional acidic pills. Moreover...
5 pages, 1 figure, 1 table, 4 schemes.-- Printed version published Nov 7, 2005.; The one-pot radical fragmentation–phosphorylation reaction of α-amino acids and β-amino alcohols affords α-amino phosphonates in good yields. The reaction was applied to the synthesis of potentially bioactive phosphonates.; This work was supported by the Research Programme
PPQ2003-01379 of the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerios de Ciencia y Tecnología y de Educación y Ciencia, Spain. We also acknowledge financial support from FEDER funds. We are especially indebted to FAES FARMA S.A. for a contract to J.A.G. and a fellowship
The reductive deoxygenation of acyl phosphonates using a Wolff−Kishner-like sequence is described. This transformation allows direct access to alkyl phosphonates from acyl phosphonates at room temperature. The method can be combined with acyl phosphonate synthesis into a one pot, four-step procedure for the conversion of carboxylic acids into alkyl phosphonates. The methodology works well for a variety of aliphatic acids and shows a functional group tolerance similar to that of other hydrazone-forming reactions.
Some imines were synthesized by the reaction of 5-amino 1-naphthol with substituted aromatic aldehydes in ethanol under reflux conditions. Dialkyl phosphites underwent addition with aromatic imines to give novel α-amino phosphonates. All the title compounds were characterized by elemental analysis, IR, ¹H, 13C, 31P NMR and mass spectral data. All the newly-synthesized compounds (4a-j) exhibited moderate antibacterial and antifungal activity.