Phosphonic Acid Analogues Research Articles

A Supramolecular Ladderlike Structure Formed by the Auto-Assembly of Benzene-1,3,5-triphosphonic Acid

Benzene-1,3,5-triphosphonic acid 1, which is the phosphonic acid analogue of trimesic acid, forms a columnar packing in the solid state that is characterized by strong hydrogen bonds (contact distances O···O ranging from 2.55 to 2.60 Å) and π-stacking (d(Ar···Ar) = 3.89 and 3.69 Å) involving the aromatic rings, thus designing an organic supramolecular ladder structure by auto-assembly.

A novel diketo phosphonic acid that exhibits specific, strand-transfer inhibition of HIV integrase and anti-HIV activity

We have synthesized novel phosphonic acid analogues of β-diketo acids. Interestingly, the phosphonic acid isostere, 2, of our anti-HIV compound, 1, was an inhibitor of only the strand transfer step, in stark contrast to 1. Compound 2 had lower anti-HIV activity than 1, but was more active and less toxic than the phosphonic acid analogue of L-708906. These isosteric compounds represent the first examples of β-diketo phosphonic acids of structural, synthetic, and antiviral interest.

Tandem Addition of Trialkyl Phosphites to α,β-Unsaturated Imines: A Comparison with Silylated Phosphites

Trialkyl phosphites were evaluated for addition reactions to alpha,beta-unsaturated imines. An acidic medium is required to allow consecutive 1,4- and 1,2-addition to occur. In this manner, 3-phosphonyl-1-aminophosphonates, phosphonic acid analogues of glutamate, are obtained in good yields (32-90%). The reaction is mainly influenced by the steric bulk of the nitrogen substituent: less steric N-substituents lead to better yields of the tandem adducts.

Synthesis and Antiviral Evaluation of Novel Cyclopropyl Nucleosides, Phosphonate Nucleosides and Phosphonic Acid Nucleosides

Novel phenyl-branched cyclopropyl nucleosides, phosphonates, and phosphonic acid analogues were designed and synthesized as potential antiviral agents. Coupling of the mesylate 10 with natural bases (U, T, C, A) and desilylation/hydrolysis afforded a series of novel cyclopropyl nucleosides 15-18. Phosphonate and phosphonic acid nucleosides 22-29 were also readily synthesized from the mesylate 21. The synthesized compounds were evaluated for their antiviral activity against various viruses such as HIV-1, HSV-1, HSV-2, and HCMV.

Asymmetric synthesis of phosphonic acid analogues for acylcarnitine

Phosphonic acid analogues of acylcarnitine were prepared in an optically active form expecting CPT I inhibitory activities. The synthetic methodology was based on catalytic asymmetric dihydroxylation of β,γ-unsaturated phosphonates and subsequent regioselective amination via the cyclic sulfates.

Synthesis of Chiral γ‐Amino‐β‐hydroxyphosphonate Derivatives from Unsaturated Phosphonates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Flexible, Efficient Synthesis of (±)-Carbocyclic Phosphonic Acid Nucleoside Derivatives

An efficient and flexible synthesis of cyclopentane and hydroxylated cyclopentane phosphonic acid analogues is described. The key step involves the opening of an epoxide with either a nu­cleoside base or a selenyl anion to access the target molecules.

Synthesis of Chiral γ-Amino-β-hydroxyphosphonate Derivatives from Unsaturated Phosphonates

γ-Amino-β-hydroxyphosphonates, useful intermediates for the synthesis of phosphonic acid analogues of carnitine, were prepared as their protected derivatives in an enantioselective manner from β,γ-unsaturated phosphonatesthrough asymmetric dihydroxylation and subsequent regioselective amination via the cyclic sulfates.

Potent Inhibition of Ribonuclease A by Oligo(vinylsulfonic Acid)

Ribonuclease A (RNase A) can make multiple contacts with an RNA substrate. In particular, the enzymatic active site and adjacent subsites bind sequential phosphoryl groups in the RNA backbone through Coulombic interactions. Here, oligomers of vinylsulfonic acid (OVS) are shown to be potent inhibitors of RNase A that exploit these interactions. Inhibition is competitive with substrate and has Ki = 11 pm in assays at low salt concentration. The effect of salt concentration on inhibition indicates that nearly eight favorable Coulombic interactions occur in the RNase A.OVS complex. The phosphonic acid and sulfuric acid analogs of OVS are also potent inhibitors although slightly less effective. OVS is also shown to be a contaminant of MES and other buffers that contain sulfonylethyl groups. Oligomers greater than nine units in length can be isolated from commercial MES buffer. Inhibition by contaminating OVS is responsible for the apparent decrease in catalytic activity that has been observed in assays of RNase A at low salt concentration. Thus, OVS is both a useful inhibitor of RNase A and a potential bane to chemists and biochemists who use ethanesulfonic acid buffers.

Phosphinic, phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABA C receptor antagonists

A number of amino acids bioisosterically derived from the specific GABA A agonist, isonipecotic acid, were electrophysiologically characterized as antagonists at GABA C ρ 1 receptors expressed in Xenopus oocytes. The phosphinic acid analogue of isonipecotic acid, piperidin-4-ylphosphinic acid ( 2), was comparable with the standard GABA C antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), in terms of potency and GABA C versus GABA A receptor selectivity. Whereas the phosphonic acid analogue, piperidin-4-ylphosphonic acid ( 4), was at least an order of magnitude weaker than piperidin-4-ylphosphinic acid as a GABA C antagonist, the seleninic acid analogue, piperidin-4-ylseleninic acid (SEPI, 6), was the most potent and selective GABA C antagonist within the group of isonipecotic acid derived amino acids studied.

Bis(hydroxymethyl)phosphine Oxides and Hydroxymethyl Phosphinic Acids as Phosphonic Acid Analogs

(2002). Bis(hydroxymethyl)phosphine Oxides and Hydroxymethyl Phosphinic Acids as Phosphonic Acid Analogs. Phosphorus, Sulfur, and Silicon and the Related Elements: Vol. 177, No. 8-9, pp. 2221-2222.

Phosphonic Acid Analogues of Tyrosine and Dihydroxyphenylalanne (DOPA) as Tyrosinase Inhibitors

Phosphonic Acid Analogues of Tyrosine and Dihydroxyphenylalanne (DOPA) as Tyrosinase Inhibitors

Determination of strong binding chelators and their metal complexes by anion-exchange chromatography and inductively coupled plasma mass spectrometry

Based on the negative charge of polycarboxylic chelators, an anion-exchange separation has been developed that is compatible with sensitive metal detection by ICP-MS. A low capacity hydrophilic polymer (AS11) was used as the anion exchanger and ammonium nitrate as the eluent. The new procedure provided high selectivity in the isocratic mode as well as a large separation window and high separation efficiency in the gradient mode. This was demonstrated for different types of chelators and their metal complexes. The aminopolycarboxylates NTA, EDTA, CDTA, DTPA, EDDS and for the EDTA derivatives HEDTA, ED3A and EDTMP, the phosphonic acid analogue of EDTA were tested. Their retention times generally depended on the charge, which was lower in 1:1 metal chelator complexes. Evaluation of the separation mechanism demonstrated that they were all separated predominantly by an anion-exchange mechanism with only a minor contribution from hydrophobic attraction. The method is useful for species identification and for predicting the charge of unknown analogous species from retention times. A gradient separation procedure achieved on-column preconcentration and matrix removal for the interference-free detection of metal chelates down to low nanomolar concentration in samples from various fields of environmental research.

Synthesis of an α-Aminophosphonate Nucleoside as an Inhibitor of S-Adenosyl- l-Homocysteine Hydrolase

A phosphonic acid analogue of S-adenosyl- l-homocysteine was prepared by a novel method and the epimeric mixture separated. Preliminary studies indicate that each epimer causes time-dependent inactivation of S-adenosyl- l-homocysteine hydrolase, however each presented distinct kinetic characteristics.

Stereoselective inhibition of glutamate carboxypeptidase by chiral phosphonothioic acids

A series of phosphonothioic acid derivatives of (S)-2-hydroxyglutarate with various alkyl or aryl ligands to the central phosphorus atom was examined for stereoselective inhibition of the glutamate carboxypeptidase, carboxypeptidase G. The inhibitory potencies of these stereoisomers were compared to corresponding synthetic phosphonic acid analogues in order to reveal the significance of the sulfur ligand of the phosphonothioic acid motif upon the inhibition of this metallopeptidase. The acquisition of the individual phosphonothioic acid diastereomers was achieved through the resolution of the respective phosphonate ester precursors. In all cases, the (+)P-diastereomers of these phosphonothioic acid derivatives of (S)-2-hydroxyglutarate were found to be more potent inhibitors of glutamate carboxypeptidase than the corresponding (−)P antipodes with the most dramatic difference observed for the butyl isomers (13.6-fold). Based upon Ki values obtained, the most potent inhibitor of the series by nearly an order of magnitude was the (+)P-n-butylphosphonothioic acid derivative, revealing specific structural and stereochemical requirements by this glutamate carboxypeptidase. With the exception of the (+)P-n-butyl analogue, the isosteric replacement of oxygen with sulfur of the phosphonic acid moiety did not enhance inhibitory potency.

Complexing properties of [(glycylamino)methyl]phosphinic acids towards Co2+, Ni2+, Cu2+ and Zn2+ ions in aqueous solutions

The complexing properties of the phosphinic acid analogues of glycylglycine ([(glycylamino)methyl]phosphinic acids) NH2CH2C(O)–NHCH2P(O)(R)(OH) [GlyGly(PR)] (R = Ph, Me and tert-Bu) towards Co2+, Ni2+, Cu2+ and Zn2+ ions in aqueous solutions are investigated using potentiometry, and absorption and EPR spectroscopies. The potentiometric results indicate different properties of the Cu2+–GlyGly(PR) systems in comparison with glycylglycine and its phosphonic acid analogue NH2CH2C(O)–NHCH2P(O)(OH)2 [GlyGly(P)]. The phosphinic dipeptides GlyGly(PR) readily form complexes with Cu2+/ligand molar ratio 1 ∶ 2 exhibiting the (Namine, Namide)2 coordination mode above pH 9 even in solutions with only a slight excess of the ligand. In the system with GlyGly, the Cu2+ complex is observed at pH 12–13 and a metal ∶ ligand ratio of 1 ∶ 500. The metal-induced deprotonation of the amide nitrogen and the extent of formation of the 1 ∶ 2 complexes depend on the acidity of the phosphinic acid group which is influenced by the substituent at the phosphorus atom. The models based on potentiometry are confirmed by spectroscopic measurements. Stability constants of the phosphinic dipeptides GlyGly(PR) with the other metal ions are the same as for glycylglycine and, therefore, the same binding pattern through the amine group and peptide oxygen is proposed. The presence of protonated complexes is assumed in all the systems studied. In the protonated complexes, the peptide is bound through the phosphinic acid group whereas the amino group remains protonated. The presence of the species in the system containing the phosphonic acid analogue of glycylglycine [GlyGly(P)] with Cu2+, which was investigated by potentiometry previously, is confirmed by EPR spectroscopy.

Novel phosphinic and phosphonic acid analogues of the anticonvulsant valproic acid

1-Propylbutylphosphinic acid 2, (1-propylbutyl)methylphosphinic acid 3 and 1-propylbutylphosphonic acid 4 have been synthesized as bioisosteres of the corresponding carboxylic acid valproate 1, which is a potent anticonvulsant. The novel phosphinic and phosphonic acids were tested for their anticonvulsant activity and were found to be inactive.

Determination of optical purity of phosphonic acid analogues of aromatic amino acids by capillary electrophoresis with α-cyclodextrin

A simple and efficient method for the determination of enantiomeric purity of structurally diverse phosphonic and phosphinic acid analogues of phenylalanine and phenylglycine using capillary electrophoresis is presented. These preliminary studies indicated that the enantiomer separation is strongly dependent on the structure of the aminophosphonic acid.

Phosphonic acid analogs of diclofenac: an Arbuzov reaction of trimethylphosphite with an ortho-quinonoid intermediate

The phosphonic acid analog of the NSAID Diclofenac was efficiently synthesized via an Arbuzov reaction between 2-(2,6-dichloroanilino)benzyl alcohol and trimethyl phosphite followed by TMSBr promoted dealkylation. Seven related phosphonic acids were synthesized using the same novel acid-catalyzed Arbuzov reaction as the key step.

1H NMR studies of rotational isomerism in phosphonic analogues of aspartic acid

Aspartic acid and its phosphonic acid analogues exhibit rotational isomerism around the C(2)-C(3) bond in solution. The characteristic vicinal proton-proton coupling constants in their H-1 NMR depend on the population of rotamers. By the use of these coupling constants, which are correlated with two different sets of parameters describing rotamer populations, namely (3)J(HH)(g) = 2.3 (or 2.4), (3)J(HH)(t) = 13.9 (or 13.3) and (3)J(HP)(g) = 4.2, (3)J(HP)(t) = 33.0 Hz, one can obtain full information on the population distribution of the rotamers in the examined compounds. Copyright (C) 2000 John Wiley & Sons, Ltd.