Phosphonic Acid Analogues Research Articles

Front Cover: Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids (Chem. Eur. J. 72/2023)

Front Cover: Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids (Chem. Eur. J. 72/2023)

Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids.

α-Aminophosphonic acids have a remarkably broad bioactivity spectrum. They can function as highly efficient transition state mimics for a variety of hydrolytic and angiotensin-converting enzymes, which makes them interesting target structures for synthetic chemists. In particular, the phosphonic acid analogs to α-aminocarboxylic acids (Pa AAs) are potent enzyme inhibitors, but many of them are only available by chiral or enzymatic resolution; sometimes only one enantiomer is accessible, and several have never been prepared in enantiopure form at all. Today, a variety of methods to access enantiopure α-aminophosphonic acids is known but none of the reported approaches can be generally applied for the synthesis of Pa AAs. Here we show that the phosphonic acid analogs of many (proteinogenic) α-amino acids become accessible by the catalytic, stereoselective asymmetric transfer hydrogenation (ATH) of α-oxo-phosphonates. The highly enantioenriched (enantiomeric excess (ee) ≥ 98 %) α-hydroxyphosphonates obtained are important pharmaceutical building blocks in themselves and could be easily converted to α-aminophosphonic acids in most studied cases. Even stereoselectively deuterated analogs became easily accessible from the same α-oxo-phosphonates using deuterated formic acid (DCO2 H).

Recent advances in the synthesis of 4′-truncated nucleoside phosphonic acid analogues

The synthesis of five series of 4′-truncated nucleoside phosphonic acid analogues is discussed in this review: (1) 4′-truncated furanose nucleoside phosphonic acid analogues; (2) 4′-truncated pyrrolidine nucleoside phosphonic acid analogues; (3) 4′-truncated carbocyclic nucleoside phosphonic acid analogues; (4) 4′-truncated isoxazole nucleoside phosphonic acid analogues; (5) 4′-truncated miscellaneous nucleoside phosphonic acid analogues. Five different ways are used to make the phosphonate moiety: (i) Michaelis-Arbuzov reaction of RX (X = Br, I, OTf) with trialkyl phosphate; (ii) Lewis acid catalyzed Michaelis-Arbuzov reaction of glycoside with trialkyl phosphite; (iii) nucleophilic addition of a dialkyl phosphite to a carbonyl group; (iv) direct coupling reaction with amino alkyl phosphonate; (v) de novo synthesis of phosphonated-isoxazole and 1,3-dioxolane heterocycles from phosphonated starting materials. Their biological activity results are briefly discussed.

Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases.

A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring.

A library of phosphonic acid analogs of phenylalanine substituted with fluorine, chlorine and trifluoromethyl moieties on the aromatic ring was synthesized and evaluated for inhibitory activity against human (hAPN) and porcine (pAPN) aminopeptidases. Fluorogenic screening indicated that these analogs are micromolar or submicromolar inhibitors, both enzymes being more active against hAPN. In order to better understand the mode of the action of the most active compounds, molecular modeling was used. It confirmed that aminophosphonic portion of the enzyme is bound nearly identically in the case of all the studied compounds, whereas the difference in activity results from the placement of aromatic side chain of an inhibitor. Interestingly, both enantiomers of the individual compounds are usually bound quite similarly.

New crystal structures of fluorinated α-aminophosphonic acid analogues of phenylglycine

The four novel phosphonic acid analogues of phenylglycine with various substituents in phenyl ring (mostly fluorine atoms) have been synthesized by using procedure of amidoalkylation of phosphorus trichloride with aromatic aldehydes and acetamide. The NMR, ESI-MS spectroscopy, and single-crystal X-Ray diffraction methods were used to characterize unusual structures: the amino-(4-trifluoromethylbenzyl)-(1), amino-(3,4-difluorobenzyl)-(2), amino-(2,4,6-trifluorobenzyl)-(3), and amino-(2-fluoro-4-hydroxybenzyl)-(4) phosphonic acids. Since the α-aminophosphonates have a potential for biological activity and could be used as building blocks in medicinal chemistry, it is important to know their detail crystal structures and properties which, in turn, may extend the knowledge on their interaction with physiologic receptors.

Phosphonic Acid Analogues of Phenylglycine as Inhibitors of Aminopeptidases: Comparison of Porcine Aminopeptidase N, Bovine Leucine Aminopeptidase, Tomato Acidic Leucine Aminopeptidase and Aminopeptidase from Barley Seeds.

The inhibitory activity of 14 racemic phosphonic acid analogs of phenylglycine, substituted in aromatic rings, towards porcine aminopeptidase N (pAPN) and barley seed aminopeptidase was determined experimentally. The obtained patterns of the inhibitory activity against the two enzymes were similar. The obtained data served as a basis for studying the binding modes of these inhibitors by pAPN using molecular modeling. It was found that their aminophosphonate fragments were bound in a highly uniform manner and that the difference in their affinities most likely resulted from the mode of substitution of their phenyl rings. The obtained binding modes towards pAPN were compared, with these predicted for bovine lens leucine aminopeptidase (blLAP) and tomato acidic leucine aminopeptidase (tLAPA). The performed studies indicated that the binding manner of the phenylglycine analogs to biLAP and tLAPA are significantly similar and differ slightly from that predicted for pAPN.

Synthesis and Aqueous Solution Properties of an Amino Bisphosphonate Methacrylate Homopolymer via RAFT Polymerization.

The present contribution reports on the synthesis via reversible addition-fragmentation chain transfer (RAFT) polymerization of a methacrylate derivative bearing an aminobisphosponate moiety as a pendant group, namely, ethyl N,N-tetramethylbis(phosphonate)-bis(methylene) amine methacrylate (MAC2NP2). The polymerization was performed by the use of cyanoisopropyl dithiobenzoate as chain transfer agent at 70 °C in various solvents with different polarities including N,N-dimethylformamide, acetonitrile, tetrahydrofuran, and in bulk. Best results were obtained in N,N-dimethylformamide where higher conversions and polymerization rates were noticed. The successful hydrolysis of the phosphonate ester groups was performed using bromotrimethylsilane with excellent yields leading to the formation of highly water soluble and pH-responsive polymers. Finally, a preliminary solution behavior study was carried out by investigating the aqueous solution properties of synthesized amino bisphosphonate methacrylate homopolymers and their phosphonic acid analogs via potentiometric titration and zeta potential measurements.

Substituted phosphonic analogues of phenylglycine as inhibitors of phenylalanine ammonia lyase from potatoes

A series of phosphonic acid analogues of phenylglycine variously substituted in phenyl ring have been synthesized and evaluated for their inhibitory activity towards potato l-phenylalanine ammonia lyase. Most of the compounds appeared to act as moderate (micromolar) inhibitors of the enzyme. Analysis of their binding performed using molecular modeling have shown that they might be bound either in active site of the enzyme or in the non-physiologic site. The latter one is located in adjoining deep site nearby the to the entrance channel for substrate into active site.

Preparation of Phosphonic Acid Analogues of Proline and Proline Analogues and Their Biological Evaluation as δ1-Pyrroline-5-carboxylate Reductase Inhibitors.

Racemic 1-hydroxy-3-butenyl-, 3-chloro-1-hydroxypropyl-, and 3-bromo-1-hydroxypropylphosphonate and the corresponding (S)-enantiomers obtained by lipase-catalyzed resolution of the respective racemic chloroacetates were subjected to functional group manipulations. These comprised ozonolysis, Mitsunobu reactions with hydrazoic acid and N-hydroxyphthalimide, alkylation of hydrazine derivative, removal of phthaloyl group followed by intramolecular substitution, and global deprotection to deliver the racemates and (R)-enantiomers (ee 92–99% by chiral high-performance liquid chromatography) of pyrrolidin-2-yl-, oxazolidin-3-yl-, oxazolidin-5-yl-, pyrazolidin-3-yl-, and 1,2-oxazinan-3-ylphosphonic acids. These phosphonic acids were evaluated as analogues of proline and proline analogues for the ability to inhibit γ-glutamyl kinase, δ1-pyrroline-5-carboxylate synthetase, and δ1-pyrroline-5-carboxylate reductase. Only the latter enzyme was inhibited by two of them at concentrations exceeding 1 mM.

A Methylidene Group in the Phosphonic Acid Analogue of Phenylalanine Reverses the Enantiopreference of Binding to Phenylalanine Ammonia-Lyases.

Aromatic amino acid ammonia‐lyases and aromatic amino acid 2,3‐aminomutases contain the post‐translationally formed prosthetic 3,5‐dihydro‐4‐methylidene‐5H‐imidazol‐5‐one (MIO) group. MIO enzymes catalyze the stereoselective synthesis of α‐ or β‐amino acid enantiomers, making these chemical processes environmentally friendly and affordable. Characterization of novel inhibitors enables structural understanding of enzyme mechanism and recognizes promising herbicide candidates as well. The present study found that both enantiomers of the aminophosphonic acid analogue of the natural substrate phenylalanine and a novel derivative bearing a methylidene at the β‐position inhibited phenylalanine ammonia‐lyases (PAL), representing MIO enzymes. X‐ray methods unambiguously determined the absolute configuration of all tested enantiomers during their synthesis. Enzyme kinetic measurements revealed the enantiomer of the methylidene‐substituted substrate analogue as being a mirror image relation to the natural l‐phenylalanine as the strongest inhibitor. Isothermal titration calorimetry (ITC) confirmed the binding constants and provided a detailed analysis of the thermodynamic driving forces of ligand binding. Molecular docking suggested that binding of the (R)‐ and (S)‐enantiomers is possible by a mirror image packing.

Extraction of Water and Speciation of Trivalent Lanthanides and Americium in Organophosphorus Extractants.

Complexes of the trivalent lanthanides and Am with di-2-ethylhexylphosphoric acid (HDEHP) dissolved in an aliphatic diluent were probed with UV-vis, X-ray absorption fine structure, and time-resolved fluorescence spectroscopy while the water concentration was determined by Karl Fischer titrations. In particular, our work focuses on the Nd-hypersensitive UV-vis absorbance region to identify the cause of changing absorbance values at 570 and 583 nm in relation to the pseudooctahedral Nd environment when coordinated with three HDEHP dimers. In contrast to recently reported interpretations, we establish that while impurities have an effect on this electronic transition band, a high water content can cause distortion of the pseudooctahedral symmetry of the six-coordinate Nd, resembling the reported spectra of the seven-coordinate Nd compounds. Extended X-ray absorption fine structure analysis of the Nd in high-concentration HDEHP solutions also points to an increase in the coordination number from 6 to 7. The spectral behavior of other lanthanides (Pr, Ho, Sm, and Er) and AmIII as a function of the HDEHP concentration suggests that water coordination with the metal likely depends on the metal's effective charge. Fluorescence data using lifetime studies and excitation and emission spectra support the inclusion of water in the Eu coordination sphere. Further, the role of the effective charge was confirmed by a comparison of the Gibbs free energies of six- and seven-coordinate La-HDEHP-H2O and Lu-HDEHP-H2O complexes using density functional theory. In contrast, HEH[EHP], the phosphonic acid analogue of HDEHP, exhibits a smaller capacity for water, and the electronic absorption spectra of Nd or Am appear to be unchanged, although the Pr spectra show a noticeable change in intensity as a function of the water content. Electronic absorption extinction coefficients of AmIII, NdIII, PrIII, SmIII, ErIII, and HoIII as a function of the HDEHP concentration are reported for the first time.

Enantiomeric α,β-diaminoethylphosphonic acids as potent inhibitors of aminopeptidases—stereoselective synthesis and biological activity

α,β-Diaminoethylphosphonic acids are efficient transition-state analogue inhibitors of alanyl aminopeptidase and endoplasmic reticulum aminopeptidase 2, biomedically important members of the M01 family of proteases. In this work, the individual enantiomers of selected inhibitors were separated and their inhibitory potency verified. The synthesis involved the use of a chiral α-methylbenzylamine to obtain diastereomeric aziridinephosphonates as key intermediates of the multistep process. The diastereomeric aziridines were resolved chromatographically, and the heterocyclic ring opened with the appropriate amines. The inhibition study revealed an interesting correlation between the absolute configuration and inhibitory activity. Certain enantiomeric phosphonic amino acid analogues exhibited inhibition constants in the nanomolar range.

Penicillin G acylase-mediated kinetic resolution of racemic 1-(N-acylamino)alkylphosphonic and 1-(N-acylamino)alkylphosphinic acids and their esters

Extensive studies on the penicillin G acylase-mediated kinetic resolution of N-acylated 1-aminoalkylphosphonic and 1-aminoalkylphosphinic acids as well as their esters were carried out to recognise the relationships between the substrate structure, reaction conditions, and the enzymatic hydrolytic deacylation efficiency and stereoselectivity. Reactivity of 1-(N-acylamino)alkylphosphonic and 1-(N-acylamino)alkylphosphinic acids and their esters in the penicillin G acylase-mediated hydrolytic deacylation reaction depends strongly on the kind of their N-acyl group, with high preference to the hydrolytic splitting of the N-phenylacetyl moiety. The initial hydrolysis rates of 1-(N-phenylacetylamino)alkylphosphonic acid dimethyl esters 2 are mostly distinctly lower in comparison with the corresponding free acids 3 and rapidly decrease with the increasing steric effect of the substituent at the α-position. In contrary to the substituents at the α-carbon, bulky substituents at the phosphorus hinder the enzymatic hydrolysis to a much lesser degree. The penicillin G acylase-mediated stereospecific hydrolysis of N-acyl group of both racemic 1-(N-acylamino)alkylphosphonic acids 3 and their dimethyl esters 2 proved to be, in most cases, a highly effective method for the kinetic resolution of these compounds. High enzyme enantioselectivity E-values exceeding 100, or synthetically useful E-values exceeding 20 (in two cases) were obtained for the N-acylated phosphonic acid analogues of alanine, phenylalanine, valine, leucine, and asparagine, as well as for their dimethyl esters, with the exception of the dimethyl ester of phosphonic analogue of valine 2e, that E-value was low (E=1.2). Also for the N-acylated H-phosphinic acid analogues of alanine, as well as phenylphosphinic acid analogue of alanine, high enzyme enantioselectivity values exceeding 100 were obtained. In contrary, E-values for both diastereomers of ethyl ester of phenylphosphinic analogue of alanine 2k were low (E=7 and 13). For the all accomplished assignments penicillin G acylase exhibited stereochemical preference for the (R)-substrate.

Synthesis and Antiviral Activity Evaluation of 2′,5′,5′-Trifluoro-Apiosyl Nucleoside Phosphonic Acid Analogs

ABSTRACTRacemic synthesis of novel 2′,5′,5′-trifluoro-apiose nucleoside phosphonic acid analogs were performed as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2, and HCMV revealed that the pyrimidine analogues have significant anti-HCMV activity.

Synthesis and Potent Anti-HCMV Activity of 2′,5′,5′-trifluoro-3′-hydroxy-apiosyl Nucleoside Phosphonic Acid Analogues

ABSTRACTAs antiviral nucleosides containing a fluorine atom at 2′-position are endowed with increased stabilization of glycosyl bond, it was of interest to investigate the influence of three fluorine atoms at 2′- and 5′-positions of apiosyl nucleoside phosphonate analogues. Various pyrimidine and purine 2′,5′,5′-trifluoro-3′-hydroxy-apiose nucleoside phosphonic acid analogues were synthesized from 1,3-dihydroxyacetone. Electrophilic fluorination of lactone was performed using N-fluorodibenzenesulfonimide. Difluorophosphonation was performed by direct displacement of triflate intermediate with diethyl(lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield nucleoside phosphonate analogues. Deprotection of diethyl phosphonates provided the final phosphonic acid sodium salts. The synthesized nucleoside analogues were subjected to antiviral screening against various viruses.

Synthesis and Antiviral Activity Evaluation of 5',5'-Difluoro-2'-methylapiosyl Nucleoside Phosphonic Acid Analogs

AbstractRacemic synthesis of novel 5',5'-difluoro-2'-methyl-apiose nucleoside phosphonic acid analogs was achieved as potentantiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl(lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfullyproceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection ofdiethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds againstvarious viruses such as HIV, HSV-1, HSV-2 and HCMV revealed that the pyrimidine analogs (cytosine, uracil, andthymine) have weak anti-HIV or HCMV activity.Keywords: Antiviral Agents; 5',5'-Difluoro-2'-methyl-apiose Nucleoside Phosphonic Acid Analogues; VorbruggenReaction 1. Introduction The modification of the nucleosides and/or sugarmoiety of a natural nucleoside is an obvious choice fordeveloping new antiviral compounds, and apiose-basednucleoside could serve this purpose.Recently, apiose 5'-nor nucleoside phosphonate

Synthesis and Anti-HIV Activity of Novel 2′-Deoxy-2′-β-Fluoro-Threosyl Nucleoside Phosphonic Acid Analogues

Novel 2′-deoxy-2′-β-fluoro-threose purine phosphonic acid analogues were designed and racemically synthesized from 2-propanone-1,3-diacetate. Condensation successfully proceeded from a glycosyl donor 9 under Vorbrüggen conditions. Cross-metathesis of vinyl analogues 13 and 23 with diethyl vinylphosphonate yielded the desired nucleoside phosphonate analogues 14 and 24, respectively. Ammonolysis and hydrolysis of phosphonates yielded the nucleoside phosphonic acid analogues 16, 19, 26, and 29. The synthesized nucleoside analogues were subjected to antiviral screening against human immunodeficiency virus (HIV)-1. Adenine analogue 18 exhibited weak in vitro activities against human immunodeficiency virus (HIV)-1.

The Synthesis of Novel 5′‐Deoxy‐3′,5′,5′‐trifluoro‐apiosyl Nucleoside Phosphonic Acid Analogs as Antiviral Agents

Racemic syntheses of novel 5′‐deoxy‐3′,5′,5′‐trifluoro‐apiose nucleoside phosphonic acid analogs were carried out from 1,3‐dihydroxyacetone, to be used as antiviral agents. Nucleophilic displacement of the triflate intermediate with diethyl (lithiodifluoromethyl)phosphonate was performed to yield the corresponding (α,α‐difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor under Vorbrüggen conditions to yield the nucleoside phosphonate analogs. Ammonolysis and hydrolysis of the phosphonates yielded the corresponding nucleoside phosphonic acid analogs. Furthermore, the lipophilic prodrug of the adenine derivative was synthesized to increase cellular uptake. The synthesized nucleoside analogs were screened for their antiviral activity against human immunodeficiency virus (HIV)‐1. The bis(SATE) prodrug of the adenine analog exhibited significant in vitro activity against HIV‐1.

Synthesis and Anti‐Retroviral Activity of Novel 5′‐Deoxy‐5′,5′‐difluoro‐threosyl Nucleoside Phosphonic Acid Analogs

Novel 5′‐deoxy‐5′,5′‐difluoro‐threose purine phosphonic acid analogs were designed and synthesized from 2‐propanone‐1,3‐diacetate. Direct displacement of the triflate intermediate 12 with diethyl (lithiodifluoromethyl)phosphonate provided the corresponding (α,α‐difluoroalkyl) phosphonate 13. Condensation successfully proceeded from a glycosyl donor 14 under Vorbrüggen conditions to provide the nucleoside phosphonate analogs 15α, 15β, 18α, and 18β, respectively. Ammonolysis and hydrolysis of the phosphonates 15β and 18β yielded the nucleoside phosphonic acid analogs 16, 17, 19b, and 20. Also, synthesis of prodrugs of adenine derivative was performed to increase cellular uptake. The synthesized nucleoside analogs were subjected to antiviral screening against human immunodeficiency virus (HIV)‐1. Bis(SATE) prodrug 22 of the adenine analog exhibited significant in vitro activity against HIV‐1.