Sphinganine‐Like Biogenesis of (E)‐1‐Nitropentadec‐1‐ene in Termite Soldiers of the Genus Prorhinotermes

In 1974, (E)‐1‐nitropentadec‐1‐ene, a strong lipophilic contact poison of soldiers of the termite genus Prorhinotermes, was the first‐described insect‐produced nitro compound. However, its biosynthesis remained unknown. In the present study, we tested the hypothesis that (E)‐1‐nitropentadec‐1‐ene biosynthesis originates with condensation of amino acids with tetradecanoic acid. By using in vivo experiments with radiolabeled and deuterium‐labeled putative precursors, we show that (E)‐1‐nitropentadec‐1‐ene is synthesized by the soldiers from glycine or L ‐serine and tetradecanoic acid. We propose and discuss three possible biosynthetic pathways.     

Enzymatic Synthesis of Enantiopure α‐ and β‐Amino Acids by Phenylalanine Aminomutase‐Catalysed Amination of Cinnamic Acid Derivatives

The phenylalanine aminomutase (PAM) from Taxus chinensis catalyses the conversion of α‐phenylalanine to β‐phenylalanine, an important step in the biosynthesis of the N‐benzoyl phenylisoserinoyl side‐chain of the anticancer drug taxol. Mechanistic studies on PAM have suggested that (E)‐cinnamic acid is an intermediate in the mutase reaction and that it can be released from the enzyme's active site. Here we describe a novel synthetic strategy that is based on the finding that ring‐substituted (E)‐cinnamic acids can serve as a substrate in PAM‐catalysed ammonia addition reactions for the biocatalytic production of several important β‐amino acids. The enzyme has a broad substrate range and a high enantioselectivity with cinnamic acid derivatives; this allows the synthesis of several non‐natural aromatic α‐ and β‐amino acids in excellent enantiomeric excess (ee >99 %). The internal 5‐methylene‐3,5‐dihydroimidazol‐4‐one (MIO) cofactor is essential for the PAM‐catalysed amination reactions. The regioselectivity of amination reactions was influenced by the nature of the ring substituent.     

Molecularly imprinted polymers for the selective recognition of l‐phenylalanine based on 1‐buty‐3‐methylimidazolium ionic liquid

To enhance the affinity of 4‐vinyl pyridine to l ‐phenylalanine (l ‐Phe) and convert the imprinting process from the aqueous phase to the organic phase, an oil‐soluble amino acid ionic liquid was introduced as a template. In this study, 1‐butyl‐3‐methylimidazolium α‐aminohydrocinnamic acid salt was first applied to prepared surface molecularly imprinted polymers (MIPs) in acetonitrile for the selective recognition of l ‐Phe. Fluorescence quenching analysis of the functional monomer on the template was investigated under different conditions to study the imprinting mechanism. Several binding studies, such as the sorption kinetics, sorption thermodynamics, and solid‐phase extraction application, and the chiral resolution of racemic phenylalanine were investigated. The binding isotherms were fitted by nonlinear regression to the Freundlich model to investigate the recognition mechanism. The affinity distribution analysis revealed that polymers imprinted by ionic liquid showed higher homogeneous binding sites than those imprinted by l ‐Phe. The competition tests were conducted by a molecularly imprinting solid‐phase extraction procedure to estimate the selective separation properties of the MIPs for l ‐Phe. The target MIP was shown to be successfully for the separation of l ‐Phe from an amino acid mixture. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42485.     

Diffusion process of amino acids in polymer supports for solid‐phase peptide synthesis as studied by pulsed‐field‐gradient spin‐echo proton nuclear magnetic resonance

The diffusion coefficient (D) values of tert‐butyloxycarbonyl‐glycine, tert‐butyloxycarbonyl‐L ‐tryptophan, tert‐butyloxycarbonyl‐L ‐phenylalanine (Boc‐Phe), and 9‐fluorenylmethoxycarbonyl‐L ‐phenylalanine in Merrifield polystyrene (MPS) gels, poly(ethylene glycol)‐grafted polystyrene (PEG–PS) gels, and crosslinked ethoxylate acrylate (CLEAR) gels, as used in solid‐phase peptide synthesis, were determined by the pulsed‐field‐gradient spin‐echo ¹H‐NMR method. From these experimental results, it was found that the amino acids in MPS gels, PEG–PS gels, and CLEAR gels with N,N‐dimethylformamide‐d₇ (DMF‐d₇) as a solvent had multidiffusion components within a measurement timescale of 10 ms. The D value of Boc‐Phe in polystyrene gels (1% divinylbenzene crosslinked) with tetrahydrofuran‐d₈ was much larger than that in the same gels with DMF‐d₇. Furthermore, the required time in which an amino acid transferred from a reactive site to a reactive site was estimated, within which the solvents and amino acids in the polymer supports diffused in the swollen beads.© 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 413–421, 2003     

Reverse Micellar Encapsulation of d‐ and l‐Enantiomers of Some Aromatic α‐Amino Acids and Nucleobases by Glucose‐Derived Non‐ionic Gemini Surfactants in Neat n‐Hexane

Novel carbohydrate‐based non‐ionic gemini surfactants consisting of two sugar head groups, two hydrophobic tails having chain lengths of C12, C14, and C16 and a flexible –(CH₂)₆– spacer were synthesized and investigated for their reverse micellar encapsulation properties. The head groups of the geminis comprise glucose entities (with reducing function blocked in a cyclic acetal group) connected through C‐6 to tertiary amines. These surfactants were explored for reverse micellar encapsulation of d ‐ and l ‐enantiomers of aromatic α‐amino acids viz. histidine (His), phenylalanine (Phe), tyrosine (Tyr) and tryptophan (Trp) in neat n‐hexane. Similar studies were carried out for encapsulation of nucleobases viz. adenine (Ade), guanine (Gua), thymine (Thy), cytosine (Cyt) and Uracil (Ura). Reverse micellar studies revealed that aromatic α‐amino acids were encapsulated in the sequence His>Tyr>Phe>Trp. In most cases, a difference in the degree of encapsulation of d ‐ and l ‐enantiomers of aromatic amino acids in reverse micellar phases of gemini amphiphiles in neat n‐hexane, was revealed. For Tyr, l ‐enantiomer was better encapsulated than its antipode, i.e., d ‐enantiomer but for Trp, d ‐enantiomer was better encapsulated then l ‐enantiomer. In the case of nucleobases, Ura was found selectively encapsulated by reverse micelles formed by these new amphiphiles.     

Palladium‐Catalyzed Allylic Alkylation of Doubly Deprotonated Carboxylic Acids

Doubly deprotonated carboxylic acids undergo smooth palladium‐catalyzed carbon alkylations with the allylic substrates methyl allyl carbonate and (E)‐methyl (pent‐3‐en‐2‐yl) carbonate to give γ,δ‐unsaturated carboxylic acids. A diastereoselective and enantioselective protocol leads to (2S,3R)‐hexenoic acid in 87% ee.     

Efficient Biosynthesis of (R)‐ or (S)‐2‐Hydroxybutyrate from l‐Threonine through a Synthetic Biology Approach

An efficient multi‐enzyme cascade reaction for the synthesis of (R)‐ or (S)‐2‐hydroxybutyric acid [(R)‐ or (S)‐2‐HB] from l ‐threonine was developed by using recombinant Escherichia coli cells expressing separately or co‐expressing l ‐threonine deaminase from Escherichia coli K‐12 (ilvA), formate dehydrogenase (FDH) from Candida boidinii and l ‐lactate dehydrogenase (l ‐LDH) from Oryctolagus cuniculus or d ‐lactate dehydrogenase (d ‐LDH) from Staphylococcus epidermidis ATCC 12228. Up to 750 mM of l ‐threonine were completely transformed to (R)‐ or (S)‐2‐HB in optically pure form (>99% ee) with high isolated yields. This one‐pot multi‐enzyme transformation provides a new practical method for the synthesis of these important optically pure compounds.

     

Combination of UDP‐Glc(NAc) 4′‐Epimerase and Galactose Oxidase in a One‐Pot Synthesis of Biotinylated Nucleotide Sugars

The enzymatic epimerization of uridine 5′‐diphospho‐α‐D ‐glucose (UDP‐Glc, 1 ) and uridine 5′‐diphospho‐N‐acetyl‐α‐D ‐glucosamine (UDP‐GlcNAc, 2 ) and the subsequent oxidation of uridine 5′‐diphospho‐α‐D ‐galactose (UDP‐Gal, 3 ) and uridine 5′‐diphospho‐N‐acetyl‐α‐D ‐galactosamine (UDP‐GalNAc, 4 ) were combined with chemical biotinylation with biotin‐ε‐amidocaproylhydrazide in a one‐pot synthesis. Analysis by CE and NMR revealed a mixture (1.0:1.4) of the biotinylated nucleotide sugars uridine 5′‐diphospho‐6‐biotin‐ε‐amidocaproylhydrazino‐α‐D ‐galactose (UDP‐6‐biotinyl‐Gal, 7) and uridine 5′‐diphospho‐6‐biotin‐ε‐amidocaproylhydrazino‐α‐D ‐glucose (UDP‐6‐biotinyl‐Glc, 9 ), respectively, in a reaction started with 1 . One product, uridine 5′‐diphospho‐6‐biotin‐ε‐amidocaproylhydrazino‐N‐acetyl‐α‐D ‐galactosamine (UDP‐6‐biotinyl‐GalNAc, 8) was formed when the reaction was initiated with 2 . It could be demonstrated for the first time that a UDP‐Glc(NAc) 4′‐epimerase (Gne from Campylobacter jejuni) and galactose oxidase from Dactylium dendroides can be used simultaneously in enzymatic catalysis. This is of particular interest since the coaction of an enzyme demanding reductive conditions and an oxygen‐dependent oxidase is unexpected.     

Dyes derived from 3‐formyl‐2(1H)‐quinolone – synthesis,spectroscopic characterisation,and their behaviour in the presence of sulfhydryl and non‐sulfhydryl amino acids

Novel dyes based on a 3‐formyl‐2(1H)‐quinolone skeleton were synthesised and characterised using ¹H nuclear magnetic resonance spectroscopy and mass spectrometry. The spectroscopic properties of these dyes, such as their absorption spectra, emission spectra, and quantum fluorescence yields, were also examined. The behaviour of the obtained compounds at a pH of 7.4 in the absence and in the presence of thiol amino acids, such as l ‐cysteine, l ‐glutathione, and N‐acetyl‐l ‐cysteine, were studied. The spectroscopic responses of the tested dyes towards other amino acids were also investigated. A reference compound was synthesised to understand the reaction mechanism between the thiols and the obtained dyes. The experimental results show that the synthesised dyes have the potential to act as sensors for thiols.     

Nuclear Magnetic Resonance Investigation of the Effect of pH on Micelle Formation by the Amino Acid‐Based Surfactant Undecyl l‐Phenylalaninate

Micelle formation by the anionic amino acid‐based surfactant undecyl l ‐phenylalaninate (und‐Phe) was investigated as a function of pH in solutions containing either Na⁺, l ‐arginine, l ‐lysine, or l ‐ornithine counterions. In each mixture, the surfactant's critical micelle concentration (CMC) was the lowest at low pH and increased as solutions became more basic. Below pH 9, surfactant solutions containing l ‐arginine and l ‐lysine had lower CMC than the corresponding solutions with Na⁺ counterions. Nuclear magnetic resonance (NMR) diffusometry and dynamic light scattering studies revealed that und‐Phe micelles with Na⁺ counterions had hydrodynamic radii of approximately 15 Å throughout the investigated pH range. Furthermore, l ‐arginine, l ‐lysine, and l ‐ornithine were found to bind most strongly to the micelles below pH 9 when the counterions were cationic. Above pH 9, the counterions became zwitterionic and dissociated from the micelle surface. In und‐Phe/l ‐arginine solution, counterion dissociation was accompanied by a decrease in the hydrodynamic radius of the micelle. However, in experiments with l ‐lysine and l ‐ornithine, micelle radii remained the same at low pH when counterions were bound and at high pH when they were not. This result suggested that l ‐arginine is attached perpendicular to the micelle surface through its guanidinium functional group with the remainder of the molecule extending into solution. Contrastingly, l ‐lysine and l ‐ornithine likely bind parallel to the micelle surface with their two amine functional groups interacting with different surfactant monomers. This model was consistent with the results from two‐dimensional ROESY (rotating frame Overhauser enhancement spectroscopy) NMR experiments. Two‐dimensional NMR also showed that in und‐Phe micelles, the aromatic rings on the phenylalanine headgroups were rotated toward the hydrocarbon core of micelle.     

Multi‐Enzymatic Synthesis of Optically Pure β‐Hydroxy α‐Amino Acids

A novel enzymatic production system of optically pure β‐hydroxy α‐amino acids was developed. Two enzymes were used for the system: an N‐succinyl L ‐amino acid β‐hydroxylase (SadA) belonging to the iron(II)/α‐ketoglutarate‐dependent dioxygenase superfamily and an N‐succinyl L ‐amino acid desuccinylase (LasA). The genes encoding the two enzymes are part of a gene set responsible for the biosynthesis of peptidyl compounds found in the Burkholderia ambifaria AMMD genome. SadA stereoselectively hydroxylated several N‐succinyl aliphatic L ‐amino acids and produced N‐succinyl β‐hydroxy L ‐amino acids, such as N‐succinyl‐L ‐β‐hydroxyvaline, N‐succinyl‐L ‐threonine, (2S,3R)‐N‐succinyl‐L ‐β‐hydroxyisoleucine, and N‐succinyl‐L ‐threo‐β‐hydroxyleucine. LasA catalyzed the desuccinylation of various N‐succinyl‐L ‐amino acids. Surprisingly, LasA is the first amide bond‐forming enzyme belonging to the amidohydrolase superfamily, and has succinylation activity towards the amino group of L ‐leucine. By combining SadA and LasA in a preparative scale production using N‐succinyl‐L ‐leucine as substrate, 2.3 mmol of L ‐threo‐β‐hydroxyleucine were successfully produced with 93% conversion and over 99% of diastereomeric excess. Consequently, the new production system described in this study has advantages in optical purity and reaction efficiency for application in the mass production of several β‐hydroxy α‐amino acids.

     

Synthesis and structure control of l‐lactic acid–glycolic acid copolymer by homo‐copolymerization

A two‐step direct melt copolymerization process of l ‐lactic acid (L ‐LA)/glycolic acid (GA) was developed: poly(l ‐lactic acid) (PLLA) and poly(glycolic acid) (PGA) with different molecular weight was first synthesized respectively by binary catalyst (tin chloride/p‐toluenesulfonic or tin chloride); and then poly(l ‐lactic‐co‐glycolic acid) (b‐PLGA) was produced by melt polymerization of the as‐prepared PLLA and PGA, wherein the composition and chain structure of b‐PLGA copolymers could be controlled by the molecular weight of PLLA. The chain structure and thermal properties of copolymers were studied by Wide‐angle X‐ray diffraction, nuclear magnetic resonance, differential scanning calorimetry, and thermogravimetric analysis. In comparison with the random PLGA (r‐PLGA) synthesized by one‐step direct melt polymerization, the average l ‐lactic blocks length (L_LA) in b‐PLGA was longer while the average glycolic blocks length (L_GA) in b‐PLGA was shorter which further resulted in the improved crystallinity and thermostability. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41566.     

One‐Pot Conversion of L‐Threonine into L‐Homoalanine: Biocatalytic Production of an Unnatural Amino Acid from a Natural One

A novel biocatalytic process for production of L ‐homoalanine from L ‐threonine has been developed using coupled enzyme reactions consisting of a threonine deaminase (TD) and an ω‐transaminase (ω‐TA). TD catalyzes the dehydration/deamination of L ‐threonine, leading to the generation of 2‐oxobutyrate which is asymmetrically converted to L ‐homoalanine via transamination with benzylamine executed by ω‐TA. To make up the coupled reaction system, we cloned and overexpressed a TD from Escherichia coli and an (S)‐specific ω‐TA from Paracoccus denitrificans. In the coupled reactions, L ‐threonine serves as a precursor of 2‐oxobutyrate for the ω‐TA reaction, eliminating the need for employing the expensive oxo acid as a starting reactant. In contrast to α‐transaminase reactions in which use of amino acids as an exclusive amino donor limits complete conversion, amines are exploited in the ω‐TA reaction and thus maximum conversion could reach 100%. The ω‐TA‐only reaction with 10 mM 2‐oxobutyrate and 20 mM benzylamine resulted in 94% yield of optically pure L ‐homoalanine (ee>99%). However, the ω‐TA‐only reaction did not produce any detectable amount of L ‐homoalanine from 10 mM L ‐threonine and 20 mM benzylamine, whereas the ω‐TA reaction coupled with TD led to 91% conversion of L ‐threonine to L ‐homoalanine.     

Indoloazepinone‐Constrained Oligomers as Cell‐Penetrating and Blood–Brain‐Barrier‐Permeating Compounds

Non‐cationic and amphipathic indoloazepinone‐constrained (Aia) oligomers have been synthesized as new vectors for intracellular delivery. The conformational preferences of the [l ‐Aia‐Xxx]_n oligomers were investigated by circular dichroism (CD) and NMR spectroscopy. Whereas Boc‐[l ‐Aia‐Gly]_2,4‐OBn oligomers 12 and 13 and Boc‐[l ‐Aia‐β³‐h‐l ‐Ala]_2,4‐OBn oligomers 16 and 17 were totally or partially disordered, Boc‐[l ‐Aia‐l ‐Ala]₂‐OBn ( 14 ) induced a typical turn stabilized by C₅‐ and C₇‐membered H‐bond pseudo‐cycles and aromatic interactions. Boc‐[l ‐Aia‐l ‐Ala]₄‐OBn ( 15 ) exhibited a unique structure with remarkable T‐shaped π‐stacking interactions involving the indole rings of the four l ‐Aia residues forming a dense hydrophobic cluster. All of the proposed FITC‐6‐Ahx‐[l ‐Aia‐Xxx]₄‐NH₂ oligomers 19 – 23 , with the exception of FITC‐6‐Ahx‐[l ‐Aia‐Gly]₄‐NH₂ ( 18 ), were internalized by MDA‐MB‐231 cells with higher efficiency than the positive references penetratin and Arg₈. In parallel, the compounds of this series were successfully explored in an in vitro blood–brain barrier (BBB) permeation assay. Although no passive diffusion permeability was observed for any of the tested Ac‐[l ‐Aia‐Xxx]₄‐NH₂ oligomers in the PAMPA model, Ac‐[l ‐Aia‐l ‐Arg]₄‐NH₂ ( 26 ) showed significant permeation in the in vitro cell‐based human model of the BBB, suggesting an active mechanism of cell penetration.     

Amphiphilic star‐shaped poly(ε‐caprolactone)‐block‐poly(l‐lysine) copolymers with porphyrin core: Synthesis,self‐assembly,and cell viability assay

Star‐shaped copolymers poly(ε‐caprolactone)‐bolck‐poly(ε‐benzyloxycarbonyl‐l ‐lysine) (SPPCL‐b‐PZLLs) with porphyrin core were synthesized by a sequential ring‐opening polymerization (ROP) of CL and Nε‐Benzyloxycarbonyl‐l ‐lysine N‐Carboxyanhydride. After the deprotection of benzyloxycarbonyl groups in polylysine blocks, the star‐shaped amphiphilic copolymers SPPCL‐b‐PLLs were obtained. These amphiphilic copolymers can self‐assemble into micelles or aggregates in aqueous solution. Investigation shows that the morphology of micelles/aggregates varied according to the change of pH values of media, indicating the pH‐responsive property of SPPCL‐b‐PLL copolymers. Furthermore, associated with conjugated porphyrin cores, the SPPCL‐b‐PLL copolymers micelles showed a certain degree of Photodynamic Therapy (PDT) effects on tumor cells, suggesting its potential application as carrier for hydrophobic drug with additional therapeutic ability of inherent porphyrin segments. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40097.     

Synthesis and characterization of degradable copoly(trans‐4‐hydroxy‐L‐proline/ϵ‐caprolactone)

The melt polycondensation reaction of N‐protected trans‐4‐hydroxy‐L ‐proline (N‐Z‐Hpr) and ?‐caprolactone (?‐CL) over a wide range of molar fractions in the feed produced new and degradable poly(N‐Z‐Hpr‐co‐?‐CL)s with stannous octoate as a catalyst. The optimal reaction conditions for the synthesis of the copolymers were obtained with 1.5 wt % stannous octoate at 140°C for 24 h. The synthesized copolymers were characterized by IR spectrophotometry, ¹H NMR, differential scanning calorimetry, and Ubbelohde viscometry. The values of the inherent viscosity (η_inh) and glass‐transition temperature (T_g) of the copolymers depended on the molar fractions of N‐Z‐Hpr. With an increase in the trans‐4‐hydroxy‐N‐benzyloxycarbonyl‐L ‐proline (N‐CBz‐Hpr) feed from 10 to 90 mol %, a decrease in η_inh from 2.47 to 1.05 dL/g, and an increase in T_g from ?48 to 49°C were observed. The in vitro degradation of these poly(N‐CBz‐Hpr‐co‐?‐CL)s was evaluated from weight‐loss measurements. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 3176–3182, 2003     

Mono‐, Di‐ and Tetra‐Cationic Surfactants as Carbon Steel Corrosion Inhibitors

Corrosion inhibition of three new synthesized cationic surfactants, N‐(2‐(((Z)‐4‐(pyridin‐4‐yl)but‐3‐en‐1‐yl)amino)ethyl)‐N‐(2‐((E)‐(pyridin‐4‐ylmethylene)amino)ethyl)dodecan‐1‐aminium bromide I(4N), N¹,N²‐didodecyl‐N¹‐((Z)‐4‐(pyridin‐4‐yl)but‐3‐en‐1‐yl)‐N²‐(2‐((E)‐(pyridin‐4‐ylmethylene)amino)ethyl)ethane‐1,2‐diaminium bromide II(4N) and 1‐dodecyl‐4‐((E)‐((2‐(dodecyl(2‐(dodecyl((Z)‐4‐(1‐dodecylpyridin‐1‐ium‐4‐yl)but‐3‐en‐1‐yl)ammonio)ethyl)ammonio)ethyl)imino)methyl)pyridin‐1‐ium bromide IV(4N) on carbon steel was investigated by weight loss, electrochemical impedance spectroscopy and polarization measurements. Results show that the synthesized cationic surfactants inhibit corrosion of carbon steel in 1 M HCl. The inhibitive action occurs by virtue of adsorption on the metal surface following a Langmuir adsorption isotherm model. Polarization curves reveal that the investigated cationic surfactants can be classified as mixed inhibitor types. The variations in the corrosion inhibition efficiency between three cationic surfactants are correlated with their chemical structures, with more hydrophobic surfactants yielding higher inhibition efficiency.     

Copper(I)‐Catalyzed Stereoselective Synthesis of (1E,3E)‐2‐ Sulfonyl‐1,3‐dienes from N‐Propargylic Sulfonohydrazones

A new method for the stereoselective synthesis of highly substituted (1E,3E)‐2‐sulfonyl‐1,3‐dienes from N‐propargylic sulfonohydrazone derivatives has been developed via copper(I)‐catalyzed [3,3] rearrangement and highly regioselective migration of the sulfonyl group.     

Evolving the N‐Terminal Domain of Pyrrolysyl‐tRNA Synthetase for Improved Incorporation of Noncanonical Amino Acids

By evolving the N‐terminal domain of Methanosarcina mazei pyrrolysyl‐tRNA synthetase (PylRS) that directly interacts with tRNA^Pyl, a mutant clone displaying improved amber‐suppression efficiency for the genetic incorporation of N^?‐(tert‐butoxycarbonyl)‐l ‐lysine threefold more than the wild type was identified. The identified mutations were R19H/H29R/T122S. Direct transfer of these mutations to two other PylRS mutants that were previously evolved for the genetic incorporation of N^?‐acetyl‐l ‐lysine and N^?‐(4‐azidobenzoxycarbonyl)‐l ‐δ,?‐dehydrolysine also improved the incorporation efficiency of these two noncanonical amino acids. As the three identified mutations were found in the N‐terminal domain of PylRS that was separated from its catalytic domain for charging tRNA^Pyl with a noncanonical amino acid, they could potentially be introduced to all other PylRS mutants to improve the incorporation efficiency of their corresponding noncanonical amino acids. Therefore, it represents a general strategy to optimize the pyrrolysine incorporation system‐based noncanonical amino‐acid mutagenesis.     

Sugar‐Based Arylsulfonamide Carboxylates as Selective and Water‐Soluble Matrix Metalloproteinase‐12 Inhibitors

Matrix metalloproteinase‐12 (MMP‐12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β‐N‐acetyl‐d ‐glucosamine moiety, were designed and synthesized as MMP‐12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP‐12 inhibitor with improved water solubility, compound 3 [(R)‐2‐(N‐(2‐(3‐(2‐acetamido‐2‐deoxy‐β‐d ‐glucopyranosyl)thioureido)ethyl)biphenyl‐4‐ylsulfonamido)‐3‐methylbutanoic acid], was identified.