Diaryl Esters Research Articles

Targeted Library of Phosphonic-Type Inhibitors of Human Neutrophil Elastase.

Despite many years of research, human neutrophil elastase (HNE) still remains an area of interest for many researchers. This multifunctional representative of neutrophil serine proteases is one of the most destructive enzymes found in the human body which can degrade most of the extracellular matrix. Overexpression or dysregulation of HNE may lead to the development of several inflammatory diseases. Previously, we presented the HNE inhibitor with kinact/KI value over 2,000,000 [M-1s-1]. In order to optimize its structure, over 100 novel tripeptidyl derivatives of α-aminoalkylphosphonate diaryl esters were synthesized, and their activity toward HNE was checked. To confirm the selectivity of the resultant compounds, several of the most active were additionally checked against the two other neutrophil proteases: proteinase 3 and cathepsin G. The developed modifications allowed us to obtain a compound with significantly increased inhibitory activity against human neutrophil elastase with high selectivity toward cathepsin G, but none toward proteinase 3.

MPI8 is Potent against SARS-CoV-2 by Inhibiting Dually and Selectively the SARS-CoV-2 Main Protease and the Host Cathepsin L.

A number of inhibitors have been developed for the SARS‐CoV‐2 main protease (MPro) as potential COVID‐19 medications but little is known about their selectivity. Using enzymatic assays, we characterized inhibition of TMPRSS2, furin, and cathepsins B/K/L by more than a dozen of previously developed MPro inhibitors including MPI1‐9, GC376, 11a, 10–1, 10–2, and 10–3. MPI1‐9, GC376 and 11a all contain an aldehyde for the formation of a reversible covalent hemiacetal adduct with the MPro active site cysteine and 10–1, 10–2 and 10–3 contain a labile ester to exchange with the MPro active site cysteine for the formation of a thioester. Our data revealed that all these inhibitors are inert toward TMPRSS2 and furin. Diaryl esters also showed low inhibition of cathepsins. However, all aldehyde inhibitors displayed high potency in inhibiting three cathepsins. Their determined IC50 values vary from 4.1 to 380 nM for cathepsin B, 0.079 to 2.3 nM for cathepsin L, and 0.35 to 180 nM for cathepsin K. All aldehyde inhibitors showed similar inhibition levels toward cathepsin L. A cellular analysis indicated high potency of MPI5 and MPI8 in inhibiting lysosomal activity, which is probably attributed to their inhibition of cathepsins. Among all aldehyde inhibitors, MPI8 shows the best selectivity toward cathepsin L. With respect to cathepsins B and K, the selective indices are 192 and 150, respectively. MPI8 is the most potent compound among all aldehyde inhibitors in cellular MPro inhibition potency and anti‐SARS‐CoV‐2 activity in Vero E6 cells. Cathepsin L has been demonstrated to play a critical role in the SARS‐CoV‐2 cell entry. By selectively inhibiting both SARS‐CoV‐2 MPro and the host cathepsin L, MPI8 potentiates dual inhibition effects to synergize its overall antiviral potency and efficacy. Due to its high selectivity toward cathepsin L that reduces potential toxicity toward host cells and high cellular and antiviral potency, we urge serious consideration of MPI8 for preclinical and clinical investigations for treating COVID‐19.

Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors.

Acylpeptide hydrolase is a serine protease, which, together with prolyl oligopeptidase, dipeptidyl peptidase IV and oligopeptidase B, belongs to the prolyl oligopeptidase family. Its primary function is associated with the removal of N-acetylated amino acid residues from proteins and peptides. Although the N-acylation occurs in 50-90 % of eukaryotic proteins, the precise functions of this modification remains unclear. Recent findings have indicated that acylpeptide hydrolase participates in various events including oxidized proteins degradation, amyloid β-peptide cleavage, and response to DNA damage. Considering the protein degradation cycle cross-talk between acylpeptide hydrolase and proteasome, inhibition of the first enzyme resulted in down-regulation of the ubiquitin-proteasome system and induction of cancer cell apoptosis. Acylpeptide hydrolase has been proposed as an interesting target for the development of new potential anticancer agents. Here, we present the synthesis of simple derivatives of (1-aminoethyl)phosphonic acid diaryl esters, phosphonic analogs of alanine diversified at the N-terminus and ester rings, as inhibitors of acylpeptide hydrolase and discuss the ability of the title compounds to induce apoptosis of U937 and MV-4-11 tumor cell lines.

Radical Reactivity of Frustrated Lewis Pairs with Diaryl Esters

Advances in the chemistry of metal-free systems known as frustrated Lewis pairs (FLPs) has exposed new reactivity of the p-block elements, particularly in small-molecule activation and catalysis. Typically, the mode of activation by FLPs has been predicated on a heterolytic two-electron process, although recently, select FLPs have been shown to participate in single-electron processes. Here, we report the reaction of diaryl substituted esters with FLPs. This results in divergent pathways, one whereby the diaryl moiety is stabilized by the Lewis basic phosphine, and the alternative pathway, wherein a single-electron transfer process occurs, generating the [Mes3P]+⋅/[C(H)Ar2]⋅ radical ion pair. The latter species undergoes a homocoupling reaction to yield tetraphenylethane derivatives. In the presence of olefins, this reactivity can be harnessed through an sp2-sp3 C–C heterocoupling reaction to generate α,β-substituted olefins. Notably, this work showcases an FLP approach to metal-free radical C–H bond activation with subsequent C–C bond formation, which also displays complementary reactivity to other approaches.

Improved Preparation of an Epoxy Substituted Reactive Mesogen

An improved manufacturing process was developed for the epoxy substituted mesogen 1 useful for the preparation of liquid crystalline materials. Notable features were telescoping of reactions, replacement of DCC with CDI for formation of a sensitive diaryl ester, and epoxidation using mCPBA in toluene. The process was validated on 100 kg scale.

One-pot melt synthesis of resorcinol based polyarylates for UV-stable coatings

Abstract A new one-pot method for the melt synthesis of polyarylates based on resorcinol and phthalic acids has been developed. The method consists in the reaction of diphenyl carbonate, phthalic acids and resorcinol using titanium butoxide as catalyst. Model reactions have shown that the diaryl ester is generated in situ by reaction of the aromatic diacid and of the aromatic diol with diphenyl carbonate. It is thus possible to obtain polymers with tailored end-groups and molecular weight, by changing the molar ratio of the monomers and the reaction conditions. More specifically, we applied this method to the synthesis of low molecular weight polymers with carboxylic end-groups, suitable for powder coating applications. The literature actually reports that resorcinol based polyarylates present an outstanding long-term UV stability and therefore COOH terminated oligomers are highly promising materials for the preparation of super-durable powder coatings. Such method can also be applied to the preparation of polyarylates with high molecular weight, that are based not only on resorcinol and phthalic acids.

Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus

Staphylococcus aureus is responsible for a variety of human infections, including life-threatening, systemic conditions. Secreted proteome, including a range of proteases, constitutes the major virulence factor of the bacterium. However, the functions of individual enzymes, in particular SplA protease, remain poorly characterized. Here, we report development of specific inhibitors of SplA protease. The design, synthesis, and activity of a series of α-aminoalkylphosphonate diaryl esters and their peptidyl derivatives are described. Potent inhibitors of SplA are reported, which may facilitate future investigation of physiological function of the protease. The binding modes of the high-affinity compounds Cbz-Phe(P) -(OC6 H4 -4-SO2 CH3 )2 and Suc-Val-Pro-Phe(P) -(OC6 H5 )2 are revealed by high-resolution crystal structures of complexes with the protease. Surprisingly, the binding mode of both compounds deviates from previously characterized canonical interaction of α-aminoalkylphosphonate peptidyl derivatives and family S1 serine proteases.

A convenient method for the one-step synthesis of phosphonic peptides

A novel and efficient method for the synthesis of peptidyl derivatives of 1-aminoalkylphosphonate diaryl esters is presented. Phosphonic peptides were obtained in one step via an amidoalkylation reaction using amides of N-protected amino acids or peptides, triphenyl phosphite, and an appropriate aldehyde.

Efficient methods for the synthesis of α-aminophosphonate fluoroalkyl esters

Two novel synthetic methods for the preparation of bis(trifluoroethyl) esters of α-aminophosphonic acids are presented. Preliminary results on the application of the compounds synthesized as inhibitors of serine proteases are also reported. Structures originating from α-aminoalkylphosphonate diaryl esters represent a novel class of serine protease inactivators.

Phosphonic Esters and their Application of Protease Control

α-Aminoalkylphosphonate diaryl esters are potent, irreversible, and highly selective site-directed inhibitors of serine proteases. The structure of the phosphonate group resembles the transition state observed during a peptide bond hydrolysis and therefore phosphonates are referred as transition state analogues. They react with the hydroxyl group of the active site serine residue leading to formation of a stable enzyme-inhibitor complex. Moreover, incorporation of a peptidyl chain at the N-terminus as well as an introduction of electron withdrawing or electron donating substituents within the ester ring structure allows for a generation of specific inhibitors that react only with target serine protease. The great advantage of the aminophosphonate diaryl esters over other classes of inhibitors is their stability in aqueous solutions, no toxicity and lack of reactivity with cysteine, threonine, aspartyl and metalloproteinases. The above resulted in their application as convenient tools to study proteases function and activity using in vivo and in vitro assays of different pathological disorders (diabetes, cancer metastasis, pulmonary diseases or hypertension); to determine the cellular localization of the proteinases (activity based probes), to be used in proteomic approach or as the reactive antigens to develop a catalytic function within the antibodies binding site. Herein we present the development of α-aminoalkylphosphonate diaryl esters as inhibitors of several serine proteases including dipeptidyl peptidase IV, cathepsin G, human neutrophil elastase, mast cell chymase and urokinase-type plasminogen activator. We have provided a historical perspective as well as a comprehensive report of the most recent studies in this field.

Convenient syntheses of novel 1-isothiocyano-alkylphosphonate diphenyl ester derivatives with potential biological activity

Herein, we describe a convenient method for the syntheses of novel 1-isothiocyano-alkylphosphonate diaryl ester derivatives and their antiproliferative activity. The syntheses are based on dithiocarbamates obtained in situ with the use of carbon disulfide under basic conditions, and their desulfurization using several different reagents, of which hydrogen peroxide proved to be the most efficient. The compounds synthesized demonstrated high antiproliferative activity against several cancer cell lines in vitro, and also showed some activity as serine protease inhibitors.

Human Neutrophil Elastase Phosphonic Inhibitors with Improved Potency of Action

Herein, we present the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of α-aminoalkylphosphonate diaryl esters as human neutrophil elastase inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin, and trypsin, was also demonstrated. We also describe the preparation of single peptide diastereomers. The most active and selective compound developed possessed a k(inact)/K(I) of 2353000 M(-1) s(-1), which is the most potent irreversible peptidyl inhibitor of human neutrophil elastase reported to date. The peptidyl inhibitors were demonstrated to be stable in PBS buffer and human plasma, as were their complexes with HNE.

Surface plasmon resonance imaging biosensor for cathepsin G based on a potent inhibitor: Development and applications

A specific surface plasmon resonance imaging (SPRI) array biosensor for the determination of the enzymatically active cathepsin G (CatG) has been developed. For this purpose, a specific interaction between an inhibitor immobilized onto a chip surface and CatG in an analyzed solution was used. The MARS-115 CatG peptidyl inhibitor containing the 1-aminoalkylphosphonate diaryl ester moiety at the C terminus and N-succinamide with a free carboxylic function was synthesized and covalently immobilized onto the gold chip surface via the thiol group (cysteamine). Atomic force microscopy was used for the observation of surface changes during the subsequent steps of chip manufacture. Optimal detection conditions were chosen. High specificity of synthesized inhibitor to CatG was proved. The precision, as well as the accuracy, was found to be well suited to enzyme determination. The sensor application for the determination of CatG in white blood cells and saliva was shown for potential diagnosis of leukemia and oral cavity diseases during the early stages of those pathological states.

Synthesis and calcium channel antagonist activity of new 1,4-dihydropyridine derivatives containing dichloroimidazolyl substituents.

A group of dialkyl, dicycloalkyl and diaryl ester analogues of nifedipine (CAS 21829-25-4), in which the ortho-nitrophenyl group at position 4 is replaced by a 4,5-dichloroimidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters in alkyl esters series showed that increasing the length of the methylene chain in C3 and C5 ester substituents (from n = 0 to n = 2) increased the activity. When increasing of the length was accompanied by increase of the hindrance, the activity decreased. In the unsymmetrical diester series, the results showed when R1 is a small substituent (R1 = Me), increasing of the lipophilic property in R2 substituent increases the activity if this high lipophilicity is not accompanied by steric hindrance. The results demonstrate that in the unsymmetrical series, several compounds (benzyl methyl, benzyl isopropyl and cyclohexyl ethyl) had activity similar to that of the reference drug nifedipine. In symmetrical diesters compounds, the most active compound was the diphenethyl ester derivative being more active than nifedipine. These structure-activity data indicate that the 4-(4,5-dichloroimidazolyl) moiety is the bioisoester of 3-nitrophenyl and 2,3-dichlorophenyl moieties.

Synthesis of novel chiral bidentatephosphite ligands derived from the pyranoside backbone of monosaccharides and their application in the Cu-catalyzed conjugate addition of dialkylzinc to enones

A series of novel bidentatephosphite ligands, derived from methyl 3,6-anhydro-α- d-glucopyranoside and chlorophosphoric acid diaryl ester, were easily synthesized. These ligands were successfully employed in the Cu-catalyzed asymmetric conjugate 1,4-addition of the organozinc reagents diethylzinc and/or dimethylzinc to enones. The stereochemically matched combination of glucopyranoside and ( R)-H 8-binaphthyl in ligand 2,4-bis{[( R)-1,1′-H 8-binaphthyl-2,2′-diyl] phosphite}-methyl 3,6-anhydro-α- d-glucopyranoside was essential to afford 85% ee for 3-ethylcyclohexanone with an ( S)-configuration in THF, using Cu(OTf) 2 as a catalytic precursor. When the reaction was carried out at lower temperatures, changing from −10 to −80 °C, a marginal influence of the temperature on the enantioselectivity of the reaction was observed. The presence of the methyl substituent at the 1-position of the glucopyranoside skeleton had a negative effect on the enantioselectivity in the 1,4-addition of ZnEt 2 to acyclic enones.

Facile synthesis of symmetrical 3,3-diarylacrylates by a Heck-Matsuda reaction: an expedient route to biologically active indanones

A simple and straightforward synthesis of symmetrical 3,3-diarylacrylates based on a Heck-Matsuda reaction of arenediazonium salts bearing electron-donating groups with methylacrylates is described. The reaction employs Pd(OAc)2 as catalyst and goes to completion within 1h affording the corresponding unsaturated diaryl esters in good to high yields. This method permitted the expeditious and efficient synthesis of the anticancer 3-arylindanone 5 in two operative steps in 43% overall yield.

Simple phosphonic inhibitors of human neutrophil elastase

Herein, we describe the synthesis and resulting activity of a complex series of α-aminophosphonate diaryl esters as irreversible human neutrophil elastase inhibitors and their selectivity preference for human neutrophil elastase over several other serine proteases such as porcine pancreatic elastase, trypsin, and chymotrypsin. We synthesized and examined the inhibitory potency of several new simple Cbz-protected α-aminoalkylphosphonate diaryl esters that yielded several new HNE inhibitors, where one of the obtained compounds Cbz-Val(P)(OC(6)H(4)-4-COOMe)(2) displayed an apparent second-order inhibition value at 33,015 M(-1) s(-1).

Phosphonic pseudopeptides as human neutrophil elastase inhibitors—a combinatorial approach

Here we present a simple and rapid method for the construction of phosphonic peptide mimetic inhibitor libraries-products of Ugi and Passerini multicomponent condensations-leading to the selection of new biologically active phosphonic pseudopeptides. As the starting isonitriles, 1-isocyanoalkylphosphonate diaryl ester derivatives were applied. The structure of the synthesized inhibitors was designed to target human neutrophil elastase, a serine protease whose uncontrolled activity may lead to development of several pathophysiological states such as rheumatoid arthritis, cystic fibrosis or tumor growth and invasion. After screening the inhibitory activity of our constructed libraries, the most active compounds were synthesized as single molecules. One of the obtained inhibitors, Cbz-Met-O-Met-Val(P)(OC(6)H(4)-p-Cl)(2), displayed apparent second-order inhibition value at 40,105M(-1)s(-1) as the diastereomers mixture. Inhibition potency and selectivity of action toward other serine proteases as well as the results of initial in vitro experiments regarding inhibitors influence on cancer cell proliferation are presented.

ChemInform Abstract: Photolysis of Aryl Esters of Tri- and Tetracoordinate Phosphorus Compounds.

Abstract Upon. UV excitation in methanol, some diaryl esters of alkyl- or alkenylphosphonates underwent an elimination of two aryl groups to give biaryls and the corresponding alkyl- or alkenylphosphonic acids. Tris(4-methoxyphenyl) phosphite also underwent a similar elimination to give 4,4′-dimethoxybiphenyl and 4-methoxyphenyl phosphonate. This interesting biaryl elimination was confirmed to proceed via a singlet intramolecular excimer by means of fluorescence spectra and Stern-Volmer analysis.

ChemInform Abstract: Preparation and Photolysis of Diaryl Esters of Acetylenedicarboxylic Acid.

Abstract Two diaryl acetylenedicarboxylates 1 a,b have been prepared in moderate yields by direct reaction of acetylenedicarboxylic acid with the corresponding phenols catalyzed by sulfuric or p -toluenesulfonic acids and also through acetylenedicarbonyl chloride. The accompanying by-products have been characterized. Attempted esterification using N,N′-dicyclohexylcarbodiimide as condensing agent gives an asymmetric ester amide 11a and a substituted uracil 12a . Photolysis of the aryl esters 1 a,b in benzene solution affords the benzocoumaran-3-ones 14a,b . In the case of 1b , minor amounts of a polycyclic condensed 4-chromanone 17b have also been observed. These results shows that the nature of the substituent attached at the β-position of the C  C triple bond plays an important role in the cyclization of o -hydroxyaryl ethynyl ketones.