Melamine salt of bis(methylol)phosphinic acid (melaphene) as a regulator of Rauwolfia serpentina specialized metabolism.
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Dose-Response Relationship, Drug↗
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Regio- and diastereoselective preparation of tetrahydrobenzo[c]-1-aza-2lambda(5)-phospholes through dearomatization cyclization of lithiated N-benzyl-N-alkyl(diphenyl)phosphinamides. Synthesis of gamma-(N-alkylamino)phosphinic acids.
A study of the protonation of the cycloadducts derived from the dearomatization reaction of lithiated N-alkyl-N-benzyldiphenylphosphinamides has been carried out. The regio- and stereoselectivity of the process has been analyzed in terms of the size of the N-alkyl substituent, the acidity and size of the protonating reagent, and the cosolvent used. The optimization of these variables allowed the preparation of tetrahydrobenzo[c]-1-aza-2lambda(5)-phospholes containing a 1,3-cyclohexadiene or 1,4-cyclohexadiene system with moderate to excellent regio- and stereocontrol. The heterocycles were readily hydrolyzed, affording gamma-(N-alkylamino)diphenylphosphinic acids with the functionalities linked to a cyclohexadiene substructure.
Amides↗
Enantiodifferentiation of N-benzyloxycarbonylaminophosphonic and phosphinic acids and their esters using cyclodextrins by means of capillary electrophoresis.
Capillary electrophoresis was successfully applied for separation of the enantiomers of N-benzyloxycarbonyl-alpha-aminophosphonic and alpha-aminophosphinic acids as well as their ethyl and phenyl monoesters with the use of a range of commercially available cyclodextrins (alpha, beta and hydroxypropyl-gamma-cyclodextrins) as chiral selectors. The dependence of effectiveness of separation on type and concentration of these chiral selectors as well as on pH of background electrolyte was examined in some detail.
Cyclodextrins↗
Studies on the biosynthesis of bialaphos (SF-1293) Part 3. Production of phosphinic acid derivatives, MP-103, MP-104 and MP-105, by a blocked mutant of Streptomyces hygroscopicus SF-1293 and their roles in the biosynthesis of bialaphos.
During biosynthetic studies on bialaphos to reveal the formation mechanisms of carbon-phosphorous bonds in detail, three new metabolites containing a H-P-C bond structure were isolated from the fermentation broth of a mutant of Streptomyces hygroscopicus SF-1293. Based on the spectroscopic analysis, the structures of these compounds have been determined as shown in Fig. 1. Transformation experiments of these metabolites to bialaphos suggested that the reduction of the phosphorous atom in phosphate will take place at an early biosynthetic stage.
Biotransformation↗
A novel site-directed affinity reagent for cross-linking human hemoglobin: bis[2-(4-phosphonooxyphenoxy)carbonylethyl]phosphinic acid.
Bis[2-(4-phosphonooxyphenoxy)carbonylethyl]phosphinc acid (BPPCEP) was prepared and evaluated as a site-directed affinity reagent for cross-linking human hemoglobin. It was synthesized in four steps starting from 4-benzyloxyphenol and was converted to its pentasodium salt so as to afford efficient cross-linking in an aqueous medium. The reagent was found to specifically cross-link human hemoglobin A(0) in the beta-cleft chains under oxygenated reaction conditions at neutral pH. The amino acid residues involved in the cross-linking were determined by mass spectral analyses of tryptic digest fragments of cross-linked hemoglobin, employing a MALDI-TOF mass spectrometer. The MS analyses suggested that the most likely amino acids involved in the cross-links are Val-1 or Lys-82 present on one of the beta subunits and Lys-82 or Lys-144 on the other. Molecular modeling studies performed on the reagent-HbA(0) complex corroborated the conclusions reached by MALDI-MS analyses. The oxygen equilibrium measurements of the three major BPPCEP-cross-linked Hb products, isolated and purified by preparative cation exchange chromatography, exhibited oxygen affinity (P(50)) values of 14.5, 12.1, and 15.5 Torr as compared with the P(50) of 13.1 Torr for cell-free hemoglobin. The oxygen-binding cooperativity of the modified products, as determined by the Hill coefficient generated from the Hill plots of the respective P(50) values, coupled with the absence of sigmoidal shape of the O(2) equilibrium curves, was considerably lower than that of the native hemoglobin.
Cross-Linking Reagents↗
Potent inhibition of human folylpolyglutamate synthetase by a phosphinic acid mimic of the tetrahedral reaction intermediate.
A phosphorous-containing pseudopeptide folate analog (Valiaeva et al., J Org Chem 2001;66:5146-54) was designed to mimic the tetrahedral intermediate formed in the ATP-dependent reaction catalyzed by folylpolyglutamate synthetase (FPGS). This analog, methotrexate-phosphinate (MTX-phosphinate; 4-amino-4-deoxy-10-methylpteroyl-L-Glu-gamma-[psi(P(O)(OH)-CH(2))]glutarate), is a highly potent (K(is), 3.1+/-0.5 nM), competitive inhibitor of recombinant human cytosolic FPGS. Within experimental limits, FPGS inhibition was not time-dependent, and preincubation of FPGS, inhibitor, and ATP did not potentiate the inhibition. These results suggest that slow phosphorylation to produce a more potent inhibitor form is not involved. MTX-phosphinate was not growth inhibitory to human CCRF-CEM leukemia cells at 1 microM (70-fold above the concentration of MTX giving 50% growth inhibition), probably because of poor transport. Because of its exceedingly high potency as an FPGS inhibitor, MTX-phosphinate represents a lead structure from which cell-permeable analogs may be developed to test the hypothesis that FPGS inhibition is therapeutically efficacious.
Cell Division↗
[2+1] cycloadditions of terminal alkynes to norbornene derivatives catalyzed by palladium complexes with phosphinous acid ligands.
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Alkynes↗
Syntheses and Crystal Structures of the New Zinc Phosphonates Zn(O(3)PCH(2)P(O)(R)(C(6)H(5))).xH(2)O, Based on Mixed Phosphonic Acid-Phosphine Oxide Building Blocks.
The two new zinc(II) phosphonates Zn(O(3)PCH(2)P(O)(C(6)H(5))(2)) (monoclinic P2(1)/c (No. 14), a = 9.961(2) Å, b = 5.838(1) Å, c = 24.608(5) Å, beta = 101.48(3) degrees, Z = 4) and Zn(O(3)PCH(2)P(O)(CH(3))(C(6)H(5))).0.67H(2)O (monoclinic P2(1)/c (No. 14), a = 15.879(5) Å, b = 7.383(2) Å, c = 10.475(3) Å, beta = 105.01(5) degrees, Z = 4) were prepared by reaction of zinc nitrate, (R)(C(6)H(5))P(O)CH(2)PO(3)H(2) [R = C(6)H(5), CH(3)], and sodium hydroxide in water in an autoclave. For the first compound, a unidimensional arrangement is observed, while for the second, a layered structure is obtained, in relation to the size of the substituents present on the phosphine oxide moiety.
Journal Article↗
Chemoselective nucleophilic arylation and single-step oxidative esterification of aldehydes using siloxanes and a palladium-phosphinous acid as a reaction switch.
Aldehydes and siloxanes form methyl esters in a single step through mild oxidative esterification in the presence of a palladium catalyst or, alternatively, afford secondary alcohols via TBAF-promoted arylation in the absence of a catalyst at increased temperatures under otherwise identical reaction conditions.
Journal Article↗
Diastereoselective ring-closing metathesis: synthesis of P-stereogenic phosphinates from prochiral phosphinic acid derivatives.
[reaction: see text] The preparation of phosphorus-containing trienes featuring two diastereotopic vinyl moieties followed by a diastereoselective ring-closing metathesis is described. This methodology allowed for the synthesis of novel highly functionalized P-stereogenic heterocycles featuring both an exo- and an endocyclic double bond. An investigation into the factors influencing the diastereochemical outcome of the ring-closing metathesis is also presented, revealing that the geometry of the double bonds conjugated to phosphorus is important and that 1,3-stereoinduction is superior to 1,4-stereoinduction for these reactions.
Journal Article↗
[Anticholinesterase activity of alkyl esters of perfluoroalkyl phosphonic and perfluoroalkyl phosphinic acids].
It has been demonstrated that esters (RO)2P(O)X and RO(R1)P(O)X where R and R1-alkyls, X-CF3 or C2F5, irreversibly inhibited cholinesterases. Their inhibitory effect increased with the elongation of alkyl radicals from CH3- to C4H9-, being more evident with respect to butyrylcholinesterase from horse serum than to acetylcholinesterase from human erythrocytes. It is shown that the concept on inability of esters of thiophosphoric acids to inhibit cholinesterases due to the fact that thionic sulphur (P-S) does not form a strong hydrogen bonds, cannot be applied to esters of perfluorothiophosphonic acids: (C2H5O)2P(S)CF3 inhibits cholinesterases more efficiently than (C2H5O)2P(O)CF3. One of the fluoric atoms probably forms hydrogen bond with the corresponding site of the active centre in cholinesterases, similar to phosphorylic oxygen (P-O) in case of the enzyme inhibition by esters of phosphoric acids.
Acetylcholinesterase↗
Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.
Collagenases↗
Pyrimidine-2,4,6-Triones: a new effective and selective class of matrix metalloproteinase inhibitors.
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that have been implicated in various disease processes. Different classes of MMP inhibitors, including hydroxamic acids, phosphinic acids and thiols, have been previously described. Most of these mimic peptides and most likely bind in a similar way to the corresponding peptide substrates. Here we describe pyrimidine-triones as a completely new class of metalloprotease inhibitors. While the pyrimidine-trione template is used as the zinc-chelating moiety, the substituents have been optimized to yield inhibitors comparable in their inhibition efficiency of matrix metalloproteinases to hydroxamic acid derivatives such as batimastat. However, they are much more specific for a small subgroup of MMPs, namely the gelatinases (MMP-2 and MMP-9).
Chelating Agents↗
Determination of the degradation compounds formed by the oxidation of thiophosphinic acids and phosphine sulfides with nitric acid.
The degradation process that takes place at room temperature when bis(2,4,4-trimethylpentyl)monothiophosphinic acid (R2P(S)OH), bis(2,4,4-trimethylpentyl)dithiophosphinic acid (R2P(S)SH) and tris(2,4,4-trimethylpentyl)phosphine sulfide (R3PS) are in contact with 5 M HNO3 has been studied by FT-Infrared, FT-Raman spectroscopy and by gas chromatography with mass spectrometry detection (GC-MS). An exposure period of ten days of the rough reagents to 5 M HNO3 causes complete oxidation of the compounds. This process mainly leads to the formation of nitrogen dioxide, elemental sulfur and the oxo-analogues of the reagents. For dilute solutions of the reagents it was observed that after 15 min of contact with phase-shaking, R2P(S)OH and R3PS are completely oxidized to yield R2P(O)OH and R3PO, respectively, whereas for R2P(S)SH, the oxidation process is less severe, because the dithioacid is still present in the oxidized mixture, the oxidation products being R2P(S)OH and R2P(O)OH.
Journal Article↗
New (alpha-Hydroxyalkyl)phosphorus Amphiphiles: Synthesis and Dissociation Constants.
Direct synthesis of free (alpha-hydroxyalkyl)phosphinic acid amphiphiles 1 can be readily realized by sonication of the heterogeneous mixture of 50% aqueous hypophosphorous acid and long-chain aldehydes in the presence of catalytic amounts of hydrochloric acid. Oxidation of these phosphinic acids by DMSO in the presence of catalytic amounts of iodine quantitatively leads to the corresponding phosphonic acids 3. IR spectra of the phosphinic acids 1 in the condensed phase and in solution reveal the presence of intra- and intermolecular associations. Dissociation constants of the phosphorus acids 1 and 3 determined by potentiometric and (31)P NMR titrations show a good correlation between the two methods. The phosphinic acid amphiphiles 1 are slightly stronger than the corresponding phosphonic acids 3. (alpha-Hydroxyalkyl)phosphonium chlorides are prepared in good yields from the phosphine PH(3) and long-chain aldehydes in acidic media.
Journal Article↗
Copper(II) complexes of some N-substituted bis(aminomethyl)phosphinate ligands. An integrated EPR study of microspeciation and coordination modes by the two-dimensional simulation method.
Copper(II) complexes of bis(aminomethyl)phosphinic acid (L1), bis(N-glycino-N-methyl)phosphinic acid (L2), bis(N-benzylglycino-N-methyl)phosphinic acid (L3), bis(l-prolino-N-methyl)phosphinic acid (L4) and bis(iminodicarboxymethyl-N-methyl)phosphinic acid (L5) were studied in aqueous solution by pH-potentiometric and electron paramagnetic resonance (EPR) spectroscopic methods. The EPR spectrum packages recorded at various ligand-to-metal concentration ratios and pH's were analyzed (after matrix rank analysis by the method of residual intensities as a complementary method) by the two-dimensional computer simulation method, which simultaneously determines the formation constants and the EPR parameters of the various (micro)species. L1 forms mono and bis complexes in different protonation states; for the other ligands, the mono complexes are always prevalent. For steric reasons, the formation of CuL is shifted to increasingly higher pH regions in the sequence L2, L3 and L4. CuLH was identified for L3, L4 and L5, and also CuLH(2) for L4 and L5. Cu(2)L(2) was found in small amounts for L3 and L4, while it predominates at pH>4 for L5. For L5, Cu(2)L(2)H(2) was also detected. For the ligands that form dimeric metal complexes in equimolar solution or at a ligand excess, Cu(2)L is formed at a metal ion excess. Ligation of the phosphinate O was suggested by indirect proofs in the protonated complexes of L1. For the ligands L2, L3 and L4, the copper(II) coordination in various species in different protonation states is reminiscent of that in the mono and bis complexes of simple amino acids. For the bis(aminomethyl)phosphinates, however, the cis positions of the amino groups in CuL are ensured by the structure of the ligand, and the isomers differ from each other in the (equatorial or axial) position of the second carboxylate group.
Journal Article↗
Thermodynamic study of lanthanide(III) complexes with bifunctional monophosphinic acid analogues of H4dota and comparative kinetic study of yttrium(III) complexes.
New bifunctional H(4)dota-like ligands with three acetic acid and one phosphinic acid pendant arms and propionate (H(5)do3ap(PrA)) or 4-aminobenzyl (H(4)do3ap(ABn)) reactive groups bound to the phosphorus atom were investigated. Potentiometric studies showed that the ligands have a similar basicity to the parent H(4)dota and the stability constants of their complexes with sodium(i) and selected lanthanide(III) ions are also similar. Formation and acid-assisted decomplexation kinetics of yttrium(III) complexes with a series of H(4)dota-like ligands (H(4)dota and its phosphinic/phosphonic acid analogues) were studied and the reactions are sensitive to a slight modification of the ligand structure. The (2-carboxyethyl)phosphinic acid derivative H(5)do3ap(PrA) and the phosphonic acid ligand H(5)do3ap form complexes faster than H(4)dota. The most kinetically inert complex is that with H(4)do3ap(ABn). Rates of complexation and decomplexation can depend on the ability to transfer proton(s) outside/inside the complex cavity and, therefore, on the hydrophobicity of the ligands. The results demonstrate that the new bifunctional ligands are suitable for labelling biomolecules with yttrium(iii) radioisotopes for utilization in nuclear medicine.
Journal Article↗
A comparison of the relative activities of a number of GABAB antagonists in the isolated vas deferens of the rat.
1. A series of GABAB receptor antagonists were tested against (+/-)-baclofen for activity on the presynaptic GABAB receptor in the rat vas deferens. 2. All the antagonists tested caused a rightward shift in the concentration-response curve to (+/-)-baclofen. 3. pA2 values calculated from full Schild analysis were as follows: phaclofen, pA2 = 4.3; delta-amino valeric acid, pA2 = 4.4; 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), pA2 = 5.0; 3-amino-propyl(n-hexyl)phosphinic acid (3-APHPA), pA2 = 4.5. 4. These results show that none of the above compounds possess potent antagonist activity at the GABAB receptor (i.e. pA2 > 6) in this peripheral tissue. In addition, the more recently available phosphinic acid antagonists, appear to offer no great advance over the GABAB antagonists previously available.
Animals↗