Search

Chlorination and mesylation at the hydroxymethyl position of deuterium-labeled N-substituted 2-(hydroxymethyl)pyrroles has been shown to occur with some involvement of a highly reactive azafulvenium species. An electron-withdrawing camphorsulfonyl substituent on nitrogen provides a chiral handle for direct analysis of the stereochemical outcome of the reactions by 1H NMR.

Olefin tethers of variable length, introduced into a natural amino acid (side-chain of Ser, Cys; N-terminus of Arg; C-terminus of Phe and Tic; and in both the side-chain and either the N- or C-terminus of Ser, Cys and Tyr), undergo metathesis on treatment with Grubbs' second generation catalyst. Side-chain linked dimers of Ser, Cys and Tyr were obtained by cross-metathesis, while olefin installation at the N- and C-terminus led to dimers of Arg and Phe (or Tic), respectively. Ring-closing metathesis of the doubly alkenylated derivatives of Ser, Cys and Tyr gave 12-, 20- and 24-membered macrocycles.

The observation in 1979 that opioid receptors interact, led to the design of bivalent ligands in an attempt to improve selectivity and affinity towards the different subtypes( i.e. mu, delta, and kappa). Dimers of monovalent 'parent' opioid structures have been evaluated and include: (a) endogenous (e.g enkephalins) or exogenous (e.g dermorphin) peptide dimer analogues (b) mixed peptidic -non-peptidic bivalent ligands and (c) dual non-peptidic dimers. Chimeric structures, using an opioid pharmacophore in combination with a a non-opioid pharmacophore, have also been prepared. The common aim in all these studies is to improve the pharmacological profile of potential analgesics to minimize common opioid-induced side effects, such as physical dependence and tolerance. Here we present a brief overview efforts to develop bivalent opioid ligands for use in pain-related research.

The redox electrochemistry of hydroquinone and Cu2+-, Ni2+-, and Fe3+-hydroquinone complexes immobilized at the SAM interface has been studied in aqueous solutions with pH 5 to 12 using cyclic voltammetry. Self-assembled monolayers were constructed with terminal hydroquinone residues designed to model marine adhesive proteins that use the DOPA (3,4-dihydroxyphenylalanine) moiety. Coordination of metal to the hydroquinone group results in a shift to the ligand oxidation potential, with the value for Delta E p,a dependent on the solution pH and identity of the metal. Cu2+ shifts the hydroquinone oxidation by -285 mV (pH 8.8), and Ni2+ by -194 mV (pH 9.16). The hydroquinone oxidation was shifted by -440 mV at pH 5 for Fe3+ solutions examined up to pH 7. By contrast, reduction of the quinone is unperturbed by the presence of Cu2+, Ni2+, and Fe3+ ions. Implications of these results to the mechanism of marine adhesion are discussed.

A series of N-heterocyclic dipeptide aldehydes 4-13 have been synthesised and evaluated as inhibitors of ovine calpain 1 (o-CAPN1) and ovine calpain 2 (o-CAPN2). 5-Formyl-pyrrole 9 (IC(50) values of 290 and 25nM against o-CAPN1 and o-CAPN2, respectively) was the most potent and selective o-CAPN2 inhibitor, displaying >11-fold selectivity. The amino acid sequences of o-CAPN1 and o-CAPN2 have been determined. Because of the lack of available structural information on the ovine calpains, in silico homology models of the active site cleft of o-CAPN1 and o-CAPN2 were developed based on human calpain 1 (h-CAPN1) X-ray crystal structure (PDB code 1ZCM). These models were used to rationalise the observed SAR for compounds 4-13 and the selectivity observed for 9. The o-CAPN2 selective inhibitor 9 (CAT0059) was assayed in an in vitro ovine lens culture system and shown to successfully protect the lens from calcium-induced opacification.

A methodology for the enantioselective synthesis of alpha-fluorinated beta2-amino acids has been developed from readily available carboxylic acids 3. Conversion to the Evan's oxazolidinone followed by enantioselective fluorination and alkylation gave 7 in high diastereomeric excess (95%). Subsequent removal of the oxazolidinone and amination at the Bn-protected hydroxyl center gave optically active alpha-fluorinated beta2-amino acids.

2-Methyl-, 2-(methoxycarbonyl)methyl-, and 2,2-[(ethoxycarbonyl)(methoxycarbonyl)]methyl-5-phenylpyrroles are prepared from the corresponding 3-butynyl and 4-(methoxycarbonyl)-3-butynyl phenyl ketone O-pentafluorobenzoyl oximes by amino Heck cyclization and tandem amino Heck carbonylation, respectively.

Synthese du compose du titre a partir d'(α-ethoxycarbonyl-P,P,P-triphenyl) phosphoniomethanure, de dichlorure d'acide oxalique et de succinate de benzhydryle

The photoswitchable N-terminal diazo and triazene-dipeptide aldehydes 8a−d, 10a,b, and 17a,b present predominantly as the (E)-isomer, which purportedly binds deep in the S3 pocket of calpain. All compounds are potent inhibitors of m-calpain, with 8b being the most active (IC50 of 35 nM). The diazo-containing inhibitors 8a, 8c, and 10a were irradiated at 340 nm to give a photostationary state enriched in the (Z)-isomer, and in all cases, these were less active. The most water soluble triazene 17a (IC50 of 90 nM) retards calpain-induced cataract formation in lens culture.

The in silico design, synthesis, and biological evaluation of ten potent type II dehydroquinase inhibitors are described. These compounds contain an anhydroquinate core, incorporated as a mimic of the enolate reaction intermediate. This substructure is attached by a variety of linking units to a terminal phenyl group that binds in an adjacent pocket. Inhibitors were synthesised from (-)-quinic acid using palladium-catalysed Stille and carboamidation chemistry. Several inhibitors exhibited nanomolar inhibition constants against type II dehydroquinases from Streptomyces coelicolor and Mycobacterium tuberculosis. These are among the most potent inhibitors of these enzymes reported to date.

Three new classes of conformationally constrained peptidomimetics, derived from modified α- and β-amino acids, have been prepared by ring closing metathesis (RCM). The first involves Cα–N′ cyclisation of the peptidic diene (23, 24, 26), the second Cβ2–N′ cyclisation (27, 28, 29), and the third N–Cβ2 cyclisation (30). The key C-centred olefin of the dienes was introduced by stereoselective α-allylation of either an α- or β-amino acid. The normal favourable influence of a tertiary amide linker in the diene towards RCM is negated by significant steric congestion, and the combination of a secondary amide linker and α,α-disubstitution promotes ring contraction on RCM.

Self-assembled thiol monolayers bound to single-crystal Au(111) surfaces containing a terminal olefin have been prepared and used to monitor electrochemically the cross-metathesis (CM) between the surface and an olefin-terminated ferrocenyl (Fc) derivative from solution over time. Mixed SAM surfaces were prepared by first adsorbing a diluent for 2 days followed by the olefinic alkanethiol for known adsorption time intervals; three diluents of varying length were used. The oxidation peak areas from the voltammetry show the CM reaction yields a maximum amount of product at 100-150 min. Beyond this time, thiol desorption is apparent and the Fc oxidation peaks diminished. A kinetic simulation of the interfacial reactions involving CM and desorption reactions are described and aided in the interpretation of the voltammetric responses. The length of the diluent and the coverage of surface olefins were important factors in limiting undesirable self-CM reactions on the surface, and a model of the relationship between the diluent and surface concentration of olefin is described. This study shows that attention to monolayer formation and reaction conditions are important parameters when maximizing CM yields on surfaces.

Calpains are Ca(2+)-dependent cysteine proteases that play an important role in cell differentiation and in apoptosis/necrosis. The overactivation of calpain is connected with a number of diseases, including cataracts and traumatic brain injury, making calpain an attractive drug target. The development of selective inhibitors of calpain has, however, proved difficult, due to a lack of detailed structural information on the protein. This difficulty has been somewhat alleviated with recent reports on the X-ray crystal structures of engineered calpains and improved biochemical characterization of the protein. This review describes properties and X-ray crystal structures of calpain, and the synthesis and binding affinities of novel calpain inhibitors.

Calpains are Ca(2+)-dependent cysteine proteases that play an important role in cell differentiation and in apoptosis/necrosis. The overactivation of calpain is connected with a number of diseases, including cataracts and traumatic brain injury, making calpain an attractive drug target. The development of selective inhibitors of calpain has, however, proved difficult, due to a lack of detailed structural information on the protein. This difficulty has been somewhat alleviated with recent reports on the X-ray crystal structures of engineered calpains and improved biochemical characterization of the protein. This review describes properties and X-ray crystal structures of calpain, and the synthesis and binding affinities of novel calpain inhibitors.

1-Benzyl-4-methylimidazoles with a range of substituents at the 2-position are prepared from O-pentafluorobenzoylamidoximes on treatment with catalytic amounts of Pd(PPh3)4 and triethylamine. The sequence provides access to optically active amino acid mimetics with a C-terminal imidazole. [structure: see text]

Analogues of chorismate and isochorismate were designed and tested as potential inhibitors in the first inhibition study against a salicylate synthase.

We present a new synthesis of SJA6017 (a potent m-calpain inhibitor) and its adaptation in order to prepare analogues in which the constituent Leu and Val residues are systematically replaced with their corresponding β-amino acids and/or the N-terminal fluorophenylsulfonyl group is replaced by a water solubilizing N-pyridin-3-ylmethoxycarbonyl group. All compounds have been assayed against m-calpain, and the best inhibitor, SJA6017, has been shown to inhibit the development of opacity in a lens culture system design to mimic cataract.

Inhibitors of varying potency have been developed for types I and II 3-dehydroquinate dehydratase (dehydroquinase), enzymes from the shikimate and quinate pathways that catalyse the dehydration of dehydroquinate to dehydroshikimate. These inhibitors have resulted from enzyme mechanistic studies and from the direct search for enzyme inhibitors with herbicidal, fungicidal or antimicrobial potential. This review discusses the design of the various inhibitors that have been produced so far and some structure-activity relationships. The majority of these inhibitors are based on dehydroquinate analogues, although some work has also been carried out on dehydroshikimate and bissulfonamides. Some discussion is also presented on advances in the synthesis of these types of compounds.

Attachment of an olefin tether to the side chain of either lysine or cysteine allows cross metathesis (CM) conjugation with olefin-containing sugar and fatty acid analogues.

In the course of the development of calpain inhibitors, we report the synthesis of eight-membered cyclic pseudo dipeptides closely related to the known inhibitor SJA6017. The ring closure was effected by metathesis of the diallyl-substituted dipeptides 6 and 7. The formation of the dipeptides under kinetic control leads to the preferential formation of the unlike diastereomer 7 over the like diastereomer 6. The relative configuration of the diastereomers was determined by NMR and modeling studies of the related cyclic compounds 8 and 9 and their derivatives. The compounds proved not to inhibit calpain.

Here we report a versatile ring-closing metathesis-based approach to 5-, 6-, and 7-membered cyclic beta-amino esters starting with simple and readily available building blocks-methionine, allylglycine, and serine-where the nature of the amino acid determines the size of the carbocyclic ring.

This so-called Wittig reaction has a number of advantages over other olefination methods; in particular, it occurs with total positional selectivity (that is, an alkene always directly replaces a carbonyl group). By comparison, a number of other carbonyl olefination reactions often occur with double-bond rearrangement. In addition, the factors that influence Eand Z-stereoselectivity are well understood and can be readily controlled through careful selection of the phosphorus reagent and reaction conditions. A wide variety of phosphorus reagents are known to participate in Wittig reactions and the exact nature of these species is commonly used to divide the Wittig reaction into three main groups, namely the ‘‘classic’’ Wittig reaction of phosphonium ylides, the Horner–Wadsworth–Emmons reaction of phosphonate anions, and the Horner–Wittig reaction of phosphine oxide anions. Each of these reaction types has its own distinct advantages and limitations, and Ph3P O Ph Ph Ph3P CH2

13C NMR and mass spectrometry studies have been used to demonstrate that the inhibition of alpha-chymotrypsin by N-sulfonylhydroxymethylpyrrole inhibitors (10) is non-covalent. Hydroxyalkylpyrroles in which an electron-withdrawing group (acyl substituent) is introduced at the alternative C2 position have been synthesised and also shown to inactivate alpha-chymotrypsin. SAR studies on this class suggests that the incorporation of phenylalanine at C2 is favoured, however, there is little gain in introducing a hydrophobic substituent at C5.

A convenient synthesis of dehydroquinic acid and its corresponding methyl ester are described. Protection of the trans diol of quinic acid, followed by PCC oxidation, gave fully protected dehydroquinic acid. This gave methyl dehydroquinate on mild acid catalyzed hydrolysis. Ester hydrolysis then gave potassium dehydroquinate which was treated with amberlite to afford dehydroquinic acid.

A versatile, stereoselective synthesis of 5-hydroxypiperidinones with substituents at N1, C3, and C6 has been developed. The sequence involves ring-closing metathesis of a diene amide and epoxidation of the resulting alkene, followed by base-mediated elimination, and finally hydrogenation.

[structure: see text] A versatile ring-closing metathesis (RCM) approach has been developed for the preparation of cis and trans cyclohexenyl-based beta-amino acids that are either unsubstituted (3) or substituted (10 and 12) at the alpha-position.

A number of routes to 3-hydroxyiminodehydroquinate 4, one of the most potent inhibitors of type II dehydroquinase that is currently known, have been investigated. Methods based on the existing literature synthesis, i.e. oxime formation of a suitably C-4 and C-5 protected methyl 3-dehydroquinate derivative were initially studied. Benzoyl protection as in 11 did give the desired product but in low overall yield. An alternative BBA protection strategy starting with 7 was successful in generating a C-4/C-5 analogue of the desired oxime 4 in high yield. Further investigation revealed that it was unnecessary to protect the dehydroquinate precursor, hence the potassium salt corresponding to oxime 4 was simply synthesised as a single isomer from methyl dehydroquinate 10.

Positive-ion fast atom bombardment mass spectra of 13 keto acid and keto ester phosphoranes were examined. All compounds gave a protonated molecular ion and characteristic peaks at m/z 303, 279, 262 and 201.

Two helical peptides, one constrained by a covalent side-chain staple, exhibit vastly different electronic properties despite adopting essentially the same backbone conformation. High level calculations confirm that these differences are due to the additional backbone rigidity imparted by the macrocyclic constraint.

Ring closing metathesis and cross metathesis approaches to a new macrocyclic peptidomimetic aldehyde 2 have been developed, with the former route being the most convenient. Aldehyde 2 is a potent inhibitor of calpain II (IC50 of 45 nM) with comparable activity to the benchmark acyclic inhibitor SJA6017 4. Both compounds contain an N-terminal 4-fluorophenylsulfonyl group. The P2 Ile analogue of 2 (16) is significantly less active (IC50 of 2000 nM) which reflects an unusually subtle importance of the P2 residue for active site binding.

The design and synthesis of a new peptide isostere which contains a trans alkene core is described. The key step involves a Wadsworth-Emmons reaction between chiral aldehyde (2S)-9a and chiral phosphonate 7 under base-sensitive conditions to give a chiral enone (2R)-24a which was reduced to afford the desired trans alkene isosteres (2R,5R)-6a and (2R,5S)-6b (Scheme 6). A potential application of this isostere in the synthesis of HIV protease inhibitors is also discussed.

The essential metabolic enzyme biotin protein ligase (BPL) is a potential target for the development of new antibiotics required to combat drug-resistant pathogens. Staphylococcus aureus BPL (SaBPL) is a bifunctional protein, possessing both biotin ligase and transcription repressor activities. This positions BPL as a key regulator of several important metabolic pathways. Here, we report the structural analysis of both holo- and apo-forms of SaBPL using X-ray crystallography. We also present small-angle X-ray scattering data of SaBPL in complex with its biotin-carboxyl carrier protein substrate as well as the SaBPL:DNA complex that underlies repression. This has revealed the molecular basis of ligand (biotinyl-5'-AMP) binding and conformational changes associated with catalysis and repressor function. These data provide new information to better understand the bifunctional activities of SaBPL and to inform future strategies for antibiotic discovery.

A number of tricyclic thiolactams, bicyclic lactams, and bicyclic thiolactams have been prepared and evaluated in vitro as inhibitors of types 1 and 2 steroid 5α-reductase. The tricycles with an 8-chloro substituent in the C-ring are nM (IC 50 ) inhibitors of type 1 steroid 5α-reductase (SR). In all the cases studied, lactams are more potent than the corresponding thiolactams. Activity against type 2 SR is greatly enhanced by a styryl (or azo) substituent on the aryl ring of the tri- and bicycles and also a related tricyclic aryl acid.

An ability to optically modulate the interactions of surfaces with functional biomolecules provides an important basis for generating new technologies including reversible biosensors, advanced medical implants, and biomolecular computers. Here we report the first example of reversible photoregulation of binding of a protease to a functional surface. A modular approach is presented with a surface-bound inhibitor containing a photoisomerizable azobenzene core to which is attached (i) appropriate protease binding functionality and (ii) a tether for surface attachment. The principle is demonstrated for alpha-chymotrypsin using a phenylalanine-based trifluoromethylketone inhibitor containing an azobenzene core and an alkyne-functionalized ethylene glycol tether, which is attached to the surface using click chemistry. UV/vis irradiation of the functional surface leads to a significant, reversible change in the amount of alpha-chymotrypsin that attaches to the surface, as measured by surface plasmon resonance.

The first nanoliter-scale regenerable ion sensor based on a microstructured optical fibre (MOF) is reported. The air holes of the MOF are functionalized with a monoazacrown bearing spiropyran to give a switchable sensor that detects lithium ions down to 100 nM in nanoliter-scale volumes. Ion binding is turned on and off on upon irradiation with light, with the sensor being unaffected by multiple rounds of photoswitching. Unbound ions are flushed from the fibre in the 'off' state to allow the sensor to be reused. The integration of an ionophore into the sensor paves the way for the development of highly specific light-based sensing platforms that are readily adaptable to sense a particular ion simply by altering the ionophore design. Refereed/Peer-reviewed

Surfaces than can switch their properties in response to external stimuli are of fundamental as well as technological interest. A prerequisite for successful switching in thin surface layers is sufficient free volume in the layer to allow molecular motions or reactions. Multilayer films grafted from aryldiazonium salts have a loosely packed structure and are good candidates for preparation of switchable surfaces. In this work, the pH-dependent wettability of carboxyphenyl films on glassy carbon surfaces is examined using water contact angle measurements. The film structure is manipulated by exposing freshly grafted films to solvents of different polarity; this influences the wettability differences observed between low- and high-pH measurements. The order of measurement of contact angles (from low pH to high, or vice versa) also influences the pH-dependent wettability. The results are consistent with film reorganization, including the formation of dimeric hydrogen-bonded structures, in response to the polarity and pH of the surrounding medium.

An unusual tetrazolodiazepin-6-one was prepared and shown, by X-ray crystallography, to adopt an essentially planar conformation about the tetrazole ring with geometry that closely approximates a cis-amide bond.

A kinetic analysis of the inhibition of malt alpha-amylase by compounds based on ascorbic acid has shown the mode of inhibition to be competitive for the parent compound, but more complex for its derivatives. We have further simplified the ascorbic acid ene-diol pharmacophore by demonstrating that dihydroxyfumaric acid is also a good inhibitor of malt alpha-amylase.

Recent developments (and some historical aspects) of protic solvent metathesis using ill-defined catalysts [e.g., RuCl3·H2O and Ru(H2O)6(tos)2] and also the more easily handled, well-defined ruthenium-based alkylidene complexes (based on 15, 16, and 17) are highlighted. Modification of these catalysts has been achieved for applications in protic solvents with the introduction of water-solubilizing ligands and by immobilization onto a suitable support. The introduction of water-solubilizing cationic and anionic phosphines is synthetically straightforward with various catalysts having been prepared in this way (see 18, 19, 29–32, 36). Immobilzation methods include tethering to a water-soluble polymeric support (see 39, 40) and modification of the benzylidene group (see 43–46). Ionic tags have also been attached to the benzylidene group (see 48–50, 52, 53). Several other approaches have also been reported as discussed here to prepare modified catalysts that display good activity in protic media (see 54–59).