Conformational Sampling by Ab Initio Molecular Dynamics Simulations Improves NMR Chemical Shift Predictions

Car–Parrinello molecular dynamics simulations were performed for <i>N</i>-methyl acetamide as a small test system for amide groups in protein backbones, and NMR chemical shifts were calculated based on the generated ensemble. If conformational sampling and explicit solvent molecules are taken into account, excellent agreement between the calculated and experimental chemical shifts is obtained. These results represent a landmark improvement over calculations based on classical molecular dynamics (MD) simulations especially for amide protons, which are predicted too high-field shifted based on the latter ensembles. We were able to show that the better results are caused by the solute–solvents interactions forming shorter hydrogen bonds as well as by the internal degrees of freedom of the solute. Inspired by these results, we propose our approach as a new tool for the validation of force fields due to its power of identifying the structural reasons for discrepancies between the experimental and calculated data

Toward the Quantum Chemical Calculation of NMR Chemical Shifts of Proteins. 2. Level of Theory, Basis Set, and Solvents Model Dependence

It has been demonstrated that the fragmentation scheme of our adjustable density matrix assembler (ADMA) approach for the quantum chemical calculations of very large systems is well-suited to calculate NMR chemical shifts of proteins [Frank et al. <i>Proteins</i> <b>2011</b>, <i>79</i>, 2189–2202]. The systematic investigation performed here on the influences of the level of theory, basis set size, inclusion or exclusion of an implicit solvent model, and the use of partial charges to describe additional parts of the macromolecule on the accuracy of NMR chemical shifts demonstrates that using a valence triple-ζ basis set leads to large improvement compared to the results given in the previous publication. Additionally, moving from the B3LYP to the mPW1PW91 density functional and including partial charges and implicit solvents gave the best results with mean absolute errors of 0.44 ppm for hydrogen atoms excluding H^N atoms and between 1.53 and 3.44 ppm for carbon atoms depending on the size and also on the accuracy of the protein structure. Polar hydrogen and nitrogen atoms are more difficult to predict. For the first, explicit hydrogen bonds to the solvents need to be included and, for the latter, going beyond DFT to post-Hartree–Fock methods like MP2 is probably required. Even if empirical methods like SHIFTX+ show similar performance, our calculations give for the first time very reliable chemical shifts that can also be used for complexes of proteins with small-molecule ligands or DNA/RNA. Therefore, taking advantage of its ab initio nature, our approach opens new fields of application that would otherwise be largely inaccessible due to insufficient availability of data for empirical parametrization

Toward the Quantum Chemical Calculation of NMR Chemical Shifts of Proteins. 3. Conformational Sampling and Explicit Solvents Model

Fragment-based quantum chemical calculations are able to accurately calculate NMR chemical shifts even for very large molecules like proteins. But even with systematic optimization of the level of theory and basis sets as well as the use of implicit solvents models, some nuclei like polar protons and nitrogens suffer from poor predictions. Two properties of the real system, strongly influencing the experimental chemical shifts but almost always neglected in the calculations, will be discussed here in great detail: (1) conformational averaging and (2) interactions with first-shell solvent molecules. Classical molecular dynamics simulations in explicit water were carried out for obtaining a representative ensemble including the arrangement of neighboring solvent molecules, which was then subjected to quantum chemical calculations. We could demonstrate with the small test system N-methyl acetamide (NMA) that the calculated chemical shifts show immense variations of up to 6 ppm and 50 ppm for protons and nitrogens, respectively, depending on the snapshot taken from a classical molecular dynamics simulation. Applying the same approach to the HA2 domain of the influenza virus glycoprotein hemagglutinin, a 32-amino-acid-long polypeptide, and comparing averaged values to the experiment, chemical shifts of nonpolar protons and carbon atoms in proteins were calculated with unprecedented accuracy. Additionally, the mean absolute error could be reduced by a factor of 2.43 for polar protons, and reasonable correlations were obtained for nitrogen and carbonyl carbon in contrast to all other studies published so far

Synthesis of 2‑Thiocarbohydrates and Their Binding to Concanavalin A

A convenient and general synthesis of 2-thiocarbohydrates via cerium ammonium nitrate oxidation of the thiocyanate ion is described. Radical addition to glycals proceeds with excellent regio- and good stereoselectivities in only one step, deprotection affords water-soluble 2-thio saccharides. Binding studies to Con A have been performed by isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR spectroscopy. The 2-thiomannose derivative binds even stronger to Con A than the natural substrate, offering opportunities for new lectin or enzyme inhibitors

Mechanistic Features of Isomerizing Alkoxycarbonylation of Methyl Oleate

The weakly coordinated triflate complex [(P^∧P)­Pd­(OTf)]⁺(OTf)⁻ (<b>1</b>) (P^∧P = 1,3-bis­(di-<i>tert</i>-butyl­phosphino)­propane) is a suitable reactive precursor for mechanistic studies of the isomerizing alkoxcarbonylation of methyl oleate. Addition of CH₃OH or CD₃OD to <b>1</b> forms the hydride species [(P^∧P)­PdH­(CH₃OH)]⁺(OTf)⁻ (<b>2-CH</b>_<b>3</b><b>OH</b>) or the deuteride [(P^∧P)­PdD­(CD₃OD)]⁺(OTf)⁻ (<b>2</b>^<b>D</b><b>-CD</b>_<b>3</b><b>OD</b>), respectively. Further reaction with pyridine cleanly affords the stable and isolable hydride [(P^∧P)­PdH­(pyridine)]⁺(OTf)⁻ (<b>2-pyr</b>). This complex yields the hydride fragment free of methanol by abstraction of pyridine with BF₃·OEt₂, and thus provides an entry to mechanistic observations including intermediates reactive toward methanol. Exposure of methyl oleate (100 equiv) to <b>2</b>^<b>D</b><b>-CD</b>_<b>3</b><b>OD</b> resulted in rapid isomerization to the thermodynamic isomer distribution, 94.3% of internal olefins, 5.5% of α,β-unsaturated ester and <0.2% of terminal olefin. Reaction of <b>2</b>-<b>pyr</b>/BF₃·OEt₂ with a stoichiometric amount of 1-¹³C-labeled 1-octene at −80 °C yields a 50:50 mixture of the linear alkyls [(P^∧P)­Pd¹³<i>C</i>H₂(CH₂)₆CH₃]⁺ and [(P^∧P)­PdCH₂(CH₂)₆¹³<i>C</i>H₃]⁺ (<b>4a</b> and <b>4b</b>). Further reaction with ¹³CO yields the linear acyls [(P^∧P)­Pd¹³C­(O)^12/13CH₂(CH₂)₆^12/13CH₃(L)]⁺ (<b>5-L</b>; L = solvent or ¹³CO). Reaction of <b>2-pyr</b>/BF₃·OEt₂ with a stoichiometric amount of methyl oleate at −80 °C also resulted in fast isomerization to form a linear alkyl species [(P^∧P)­PdCH₂(CH₂)₁₆C­(O)­OCH₃]⁺ (<b>6</b>) and a branched alkyl stabilized by coordination of the ester carbonyl group as a four membered chelate [(P^∧P)­PdCH­{(CH₂)₁₅CH₃}­C­(O)­OCH₃]⁺ (<b>7</b>). Addition of carbon monoxide (2.5 equiv) at −80 °C resulted in insertion to form the linear acyl carbonyl [(P^∧P)­PdC­(O)­(CH₂)₁₇C­(O)­OCH₃(CO)]⁺ (<b>8-CO</b>) and the five-membered chelate [(P^∧P)­PdC­(O)­CH­{(CH₂)₁₅CH₃}­C­(O)­OCH₃]⁺ (<b>9</b>). Exposure of <b>8-CO</b> and <b>9</b> to ¹³CO at −50 °C results in gradual incorporation of the ¹³C label. Reversibility of <b>7</b> + CO ⇄ <b>9</b> is also evidenced by Δ<i>G</i> = −2.9 kcal mol^–1 and Δ<i>G</i>^⧧ = 12.5 kcal mol^–1 from DFT studies. Addition of methanol at −80 °C results in methanolysis of <b>8-L</b> (L = solvent) to form the linear diester, 1,19-dimethylnonadecandioate, whereas <b>9</b> does not react and no branched diester is observed. DFT yields a barrier for methanolysis of Δ<i>G</i>^⧧ = 29.7 kcal mol^–1 for the linear (<b>8</b>) vs Δ<i>G</i>^⧧ = 37.7 kcal mol^–1 for the branched species (<b>9</b>)

Mechanistic Features of Isomerizing Alkoxycarbonylation of Methyl Oleate

The weakly coordinated triflate complex [(P^∧P)­Pd­(OTf)]⁺(OTf)⁻ (<b>1</b>) (P^∧P = 1,3-bis­(di-<i>tert</i>-butyl­phosphino)­propane) is a suitable reactive precursor for mechanistic studies of the isomerizing alkoxcarbonylation of methyl oleate. Addition of CH₃OH or CD₃OD to <b>1</b> forms the hydride species [(P^∧P)­PdH­(CH₃OH)]⁺(OTf)⁻ (<b>2-CH</b>_<b>3</b><b>OH</b>) or the deuteride [(P^∧P)­PdD­(CD₃OD)]⁺(OTf)⁻ (<b>2</b>^<b>D</b><b>-CD</b>_<b>3</b><b>OD</b>), respectively. Further reaction with pyridine cleanly affords the stable and isolable hydride [(P^∧P)­PdH­(pyridine)]⁺(OTf)⁻ (<b>2-pyr</b>). This complex yields the hydride fragment free of methanol by abstraction of pyridine with BF₃·OEt₂, and thus provides an entry to mechanistic observations including intermediates reactive toward methanol. Exposure of methyl oleate (100 equiv) to <b>2</b>^<b>D</b><b>-CD</b>_<b>3</b><b>OD</b> resulted in rapid isomerization to the thermodynamic isomer distribution, 94.3% of internal olefins, 5.5% of α,β-unsaturated ester and <0.2% of terminal olefin. Reaction of <b>2</b>-<b>pyr</b>/BF₃·OEt₂ with a stoichiometric amount of 1-¹³C-labeled 1-octene at −80 °C yields a 50:50 mixture of the linear alkyls [(P^∧P)­Pd¹³<i>C</i>H₂(CH₂)₆CH₃]⁺ and [(P^∧P)­PdCH₂(CH₂)₆¹³<i>C</i>H₃]⁺ (<b>4a</b> and <b>4b</b>). Further reaction with ¹³CO yields the linear acyls [(P^∧P)­Pd¹³C­(O)^12/13CH₂(CH₂)₆^12/13CH₃(L)]⁺ (<b>5-L</b>; L = solvent or ¹³CO). Reaction of <b>2-pyr</b>/BF₃·OEt₂ with a stoichiometric amount of methyl oleate at −80 °C also resulted in fast isomerization to form a linear alkyl species [(P^∧P)­PdCH₂(CH₂)₁₆C­(O)­OCH₃]⁺ (<b>6</b>) and a branched alkyl stabilized by coordination of the ester carbonyl group as a four membered chelate [(P^∧P)­PdCH­{(CH₂)₁₅CH₃}­C­(O)­OCH₃]⁺ (<b>7</b>). Addition of carbon monoxide (2.5 equiv) at −80 °C resulted in insertion to form the linear acyl carbonyl [(P^∧P)­PdC­(O)­(CH₂)₁₇C­(O)­OCH₃(CO)]⁺ (<b>8-CO</b>) and the five-membered chelate [(P^∧P)­PdC­(O)­CH­{(CH₂)₁₅CH₃}­C­(O)­OCH₃]⁺ (<b>9</b>). Exposure of <b>8-CO</b> and <b>9</b> to ¹³CO at −50 °C results in gradual incorporation of the ¹³C label. Reversibility of <b>7</b> + CO ⇄ <b>9</b> is also evidenced by Δ<i>G</i> = −2.9 kcal mol^–1 and Δ<i>G</i>^⧧ = 12.5 kcal mol^–1 from DFT studies. Addition of methanol at −80 °C results in methanolysis of <b>8-L</b> (L = solvent) to form the linear diester, 1,19-dimethylnonadecandioate, whereas <b>9</b> does not react and no branched diester is observed. DFT yields a barrier for methanolysis of Δ<i>G</i>^⧧ = 29.7 kcal mol^–1 for the linear (<b>8</b>) vs Δ<i>G</i>^⧧ = 37.7 kcal mol^–1 for the branched species (<b>9</b>)

Activation and Deactivation of Neutral Palladium(II) Phosphinesulfonato Polymerization Catalysts

¹³C-Labeled ethylene polymerization (pre)­catalysts [κ²-(anisyl)₂<i>P,O</i>]­Pd­(¹³CH₃)­(L) (<b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-L</b>) (L = pyridine, dmso) based on di­(2-anisyl)­phosphine benzenesulfonate were used to assess the degree of incorporation of ¹³CH₃ groups into the formed polyethylenes. Polymerizations of variable reaction time reveal that ca. 60–85% of the ¹³C-label is found in the polymer after already 1 min polymerization time, which provides evidence that the pre-equilibration between the catalyst precursor <b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-L</b> and the active species <b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-(ethylene)</b> is fast with respect to chain growth. The fraction of <b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-L</b> that initiates chain growth is likely higher than the 60–85% determined from the ¹³C-labeled polymer chain ends since (a) chain walking results in in-chain incorporation of the ¹³C-label, (b) irreversible catalyst deactivation by formation of saturated (and partially volatile) alkanes diminishes the amount of ¹³CH₃ groups incorporated into the polymer, and (c) palladium-bound ¹³CH₃ groups, and more general palladium-bound alkyl­(polymeryl) chains, partially transfer to phosphorus by reductive elimination. NMR and ESI-MS analyses of thermolysis reactions of <b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-L</b> provide evidence that a mixture of phosphonium salts (¹³CH₃)_<i>x</i>P⁺(aryl)_4–<i>x</i> (<b>2</b>–<b>7</b>) is formed in the absence of ethylene. In addition, isolation and characterization of the mixed bis­(chelate) palladium complex [κ²-(anisyl)₂<i>P,O</i>]­Pd­[κ²-(anisyl)­(^<b>13</b>CH₃)<i>P,O</i>] (<b>11</b>) by NMR and X-ray diffraction analyses from these mixtures indicate that oxidative addition of phosphonium salts to palladium(0) species is also operative. The scrambling of palladium-bound carbyls and phosphorus-bound aryls is also relevant under NMR, as well as preparative reactor polymerization conditions exemplified by the X-ray diffraction analysis of [κ²-(anisyl)₂<i>P</i>,<i>O</i>]­Pd­[κ²<b>-</b>(anisyl)­(CH₂CH₃)<i>P,O</i>] (<b>12</b>) and [κ²-(anisyl)₂<i>P,O</i>]­Pd­[κ²-(anisyl)­((CH₂)₃CH₃)<i>P,O</i>] (<b>13</b>) isolated from pressure reactor polymerization experiments. In addition, ESI-MS analyses of reactor polymerization filtrates indicate the presence of (odd- and even-numbered alkyl)­(anisyl)­phosphine sulfonates (<b>14</b>) and their respective phosphine oxides (<b>15</b>). Furthermore, 2-(vinyl)­anisole was detected in NMR tube and reactor polymerizations, which results from ethylene insertion into a palladium–anisyl bond and concomitant β-hydride elimination. In addition to these scrambling reactions, formation of alkanes or fully saturated polymer chains, bis­(chelate)palladium complexes [κ²<b>-</b><i>P,O</i>]₂Pd, and palladium black was identified as an irreversible catalyst deactivation pathway. This deactivation proceeds by reaction of palladium alkyl complexes with palladium hydride complexes [κ²<b>-</b><i>P,O</i>]­Pd­(H)­(L) or by reaction with the free ligand H­[P,O] generated by reductive elimination from [κ²<b>-</b><i>P,O</i>]­Pd­(H)­(L). The model hydride complex <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> has been synthesized in order to establish whether <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> or H­[P,O] is responsible for the irreversible catalyst deactivation. However, upon reaction with <b>1-</b>^<b>(13)</b><b>CH</b>_<b>3</b><b>-L</b> or <b>1-CH</b>_<b>2</b><b>CH</b>_<b>3</b><b>-PPh</b>_<b>3</b>, both <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> and H­[P,O] result in formation of methane or ethane, even though H­[P,O] reacts faster than <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b>. DFT calculations show that reductive elimination to form H­[P,O] and (alkyl)­[P,O] from <b>1-H/(alkyl)-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> is kinetically accessible, as is the oxidative readdition of the P–H bond of H­[P,O] and the P–anisyl bond of (alkyl)­[P,O] to [Pd­(P^{<i><b>t</b></i>}Bu₃)₂]. These calculations also indicate that for a reaction sequence comprising reductive elimination of H­[P,O] from <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> and reaction of H­[P,O] with <b>1-CH</b>_<b>3</b><b>-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b>, <b>1-CH</b>_<b>3</b><b>-dmso</b>, or <b>1-CH</b>_<b>2</b><b>CH</b>_<b>3</b><b>-PPh</b>_<b>3</b> to form methane or ethane, the rate-limiting step is reductive elimination of H­[P,O] with a barrier of 124 kJ mol^–1. However, a second reaction coordinate was found for the reaction of <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> with <b>1-CH</b>_<b>3</b><b>-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> or <b>1-CH</b>_<b>3</b><b>-dmso</b>, which evolves into bimetallic transition-state geometries with a nearly linear H-(CH₃)-Pd alignment and which exhibits a barrier of 131 or 95 kJ mol^–1 for the formation of methane

Activation and Deactivation of Neutral Palladium(II) Phosphinesulfonato Polymerization Catalysts

¹³C-Labeled ethylene polymerization (pre)­catalysts [κ²-(anisyl)₂<i>P,O</i>]­Pd­(¹³CH₃)­(L) (<b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-L</b>) (L = pyridine, dmso) based on di­(2-anisyl)­phosphine benzenesulfonate were used to assess the degree of incorporation of ¹³CH₃ groups into the formed polyethylenes. Polymerizations of variable reaction time reveal that ca. 60–85% of the ¹³C-label is found in the polymer after already 1 min polymerization time, which provides evidence that the pre-equilibration between the catalyst precursor <b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-L</b> and the active species <b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-(ethylene)</b> is fast with respect to chain growth. The fraction of <b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-L</b> that initiates chain growth is likely higher than the 60–85% determined from the ¹³C-labeled polymer chain ends since (a) chain walking results in in-chain incorporation of the ¹³C-label, (b) irreversible catalyst deactivation by formation of saturated (and partially volatile) alkanes diminishes the amount of ¹³CH₃ groups incorporated into the polymer, and (c) palladium-bound ¹³CH₃ groups, and more general palladium-bound alkyl­(polymeryl) chains, partially transfer to phosphorus by reductive elimination. NMR and ESI-MS analyses of thermolysis reactions of <b>1-</b>^<b>13</b><b>CH</b>_<b>3</b><b>-L</b> provide evidence that a mixture of phosphonium salts (¹³CH₃)_<i>x</i>P⁺(aryl)_4–<i>x</i> (<b>2</b>–<b>7</b>) is formed in the absence of ethylene. In addition, isolation and characterization of the mixed bis­(chelate) palladium complex [κ²-(anisyl)₂<i>P,O</i>]­Pd­[κ²-(anisyl)­(^<b>13</b>CH₃)<i>P,O</i>] (<b>11</b>) by NMR and X-ray diffraction analyses from these mixtures indicate that oxidative addition of phosphonium salts to palladium(0) species is also operative. The scrambling of palladium-bound carbyls and phosphorus-bound aryls is also relevant under NMR, as well as preparative reactor polymerization conditions exemplified by the X-ray diffraction analysis of [κ²-(anisyl)₂<i>P</i>,<i>O</i>]­Pd­[κ²<b>-</b>(anisyl)­(CH₂CH₃)<i>P,O</i>] (<b>12</b>) and [κ²-(anisyl)₂<i>P,O</i>]­Pd­[κ²-(anisyl)­((CH₂)₃CH₃)<i>P,O</i>] (<b>13</b>) isolated from pressure reactor polymerization experiments. In addition, ESI-MS analyses of reactor polymerization filtrates indicate the presence of (odd- and even-numbered alkyl)­(anisyl)­phosphine sulfonates (<b>14</b>) and their respective phosphine oxides (<b>15</b>). Furthermore, 2-(vinyl)­anisole was detected in NMR tube and reactor polymerizations, which results from ethylene insertion into a palladium–anisyl bond and concomitant β-hydride elimination. In addition to these scrambling reactions, formation of alkanes or fully saturated polymer chains, bis­(chelate)palladium complexes [κ²<b>-</b><i>P,O</i>]₂Pd, and palladium black was identified as an irreversible catalyst deactivation pathway. This deactivation proceeds by reaction of palladium alkyl complexes with palladium hydride complexes [κ²<b>-</b><i>P,O</i>]­Pd­(H)­(L) or by reaction with the free ligand H­[P,O] generated by reductive elimination from [κ²<b>-</b><i>P,O</i>]­Pd­(H)­(L). The model hydride complex <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> has been synthesized in order to establish whether <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> or H­[P,O] is responsible for the irreversible catalyst deactivation. However, upon reaction with <b>1-</b>^<b>(13)</b><b>CH</b>_<b>3</b><b>-L</b> or <b>1-CH</b>_<b>2</b><b>CH</b>_<b>3</b><b>-PPh</b>_<b>3</b>, both <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> and H­[P,O] result in formation of methane or ethane, even though H­[P,O] reacts faster than <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b>. DFT calculations show that reductive elimination to form H­[P,O] and (alkyl)­[P,O] from <b>1-H/(alkyl)-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> is kinetically accessible, as is the oxidative readdition of the P–H bond of H­[P,O] and the P–anisyl bond of (alkyl)­[P,O] to [Pd­(P^{<i><b>t</b></i>}Bu₃)₂]. These calculations also indicate that for a reaction sequence comprising reductive elimination of H­[P,O] from <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> and reaction of H­[P,O] with <b>1-CH</b>_<b>3</b><b>-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b>, <b>1-CH</b>_<b>3</b><b>-dmso</b>, or <b>1-CH</b>_<b>2</b><b>CH</b>_<b>3</b><b>-PPh</b>_<b>3</b> to form methane or ethane, the rate-limiting step is reductive elimination of H­[P,O] with a barrier of 124 kJ mol^–1. However, a second reaction coordinate was found for the reaction of <b>1-H-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> with <b>1-CH</b>_<b>3</b><b>-P</b>^{<i><b>t</b></i>}<b>Bu</b>_<b>3</b> or <b>1-CH</b>_<b>3</b><b>-dmso</b>, which evolves into bimetallic transition-state geometries with a nearly linear H-(CH₃)-Pd alignment and which exhibits a barrier of 131 or 95 kJ mol^–1 for the formation of methane

Discovery of Two Classes of Potent Glycomimetic Inhibitors of <i>Pseudomonas aeruginosa</i> LecB with Distinct Binding Modes

The treatment of infections due to the opportunistic pathogen <i>Pseudomonas aeruginosa</i> is often difficult, as a consequence of bacterial biofilm formation. Such a protective environment shields the bacterium from host defense and antibiotic treatment and secures its survival. One crucial factor for maintenance of the biofilm architecture is the carbohydrate-binding lectin LecB. Here, we report the identification of potent mannose-based LecB inhibitors from a screening of four series of mannosides in a novel competitive binding assay for LecB. Cinnamide and sulfonamide derivatives are inhibitors of bacterial adhesion with up to a 20-fold increase in affinity to LecB compared to the natural ligand methyl mannoside. Because many lectins of the host require terminal saccharides (<i>e.g.</i>, fucosides), such capped structures as reported here may offer a beneficial selectivity profile for the pathogenic lectin. Both classes of compounds show distinct binding modes at the protein, offering the advantage of a simultaneous development of two new lead structures as anti-pseudomonadal drugs with an anti-virulence mode of action