Microwave and flow syntheses of Pseudomonas quinolone signal (PQS) and analogues.

Expedient syntheses of Pseudomonas quinolone signal (PQS) and related structural analogues using microwave and flow methods are reported.

Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening.

The screening of large arrays of drug-like small-molecules was traditionally a time consuming and resource intensive task. New methodology developed within our laboratories provides an attractive low cost, 3D microarray-assisted screening platform that could be used to rapidly assay thousands of compounds. As a proof-of-principle the platform was exploited to screen a number of quorum sensing analogs.

3D small-molecule microarrays.

A PEG based 3D hydrogel slide was developed specifically for small-molecule microarraying purposes, which displayed improved loading capacity, signal sensitivity and spot morphology compared with a commercially available slide and comparative 2D slide.

Continuous flow based catch and release protocol for the synthesis of alpha-ketoesters.

Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of alpha-ketoesters is reported.

Fluorous tagged small molecule microarrays.

The affinity fluorous interaction between fluorous tagged small molecules and a fluoroalkyl modified glass surface was shown to facilitate the detection of protein-ligand binding interactions in the fabrication and screening of small molecule microarrays.

Fully automated flow-through synthesis of secondary sulfonamides in a binary reactor system.

A fully automated flow-through process for the production of secondary sulfonamides is presented. Primary sulfonamides were monoalkylated using a two-step "catch and release" protocol to generate library products of high purity. The automated flow synthesis platform incorporates four independent reactor columns and is able to perform automated column regeneration.

Small-molecule screening: advances in microarraying and cell-imaging technologies.

Cell-permeable small molecules can be used to modulate protein function selectively, rapidly, reversibly, and conditionally with temporal and quantitative control in biological systems. The identification of these chemical probes can require the screening of large numbers of small molecules. With the advent of new technologies, small-molecule high-throughput screening is widely available.

Immunomodulatory effects of Pseudomonas aeruginosa quorum sensing small molecule probes on mammalian macrophages.

Pseudomonas aeruginosa produces the quorum sensing signalling molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). This natural product not only coordinates production of virulence factors by the bacterium, but also has immunomodulatory effects on the host organism. Immunomodulatory small molecules are valuable for immunology research and are potential therapeutics for autoimmune diseases such as rheumatoid arthritis, and immunosuppressive drugs following organ transplants.

The use of a continuous flow-reactor employing a mixed hydrogen-liquid flow stream for the efficient reduction of imines to amines.

Imines have been reduced to amines in high yield, and with excellent chemoselectivity, by catalytic hydrogenation in a continuous flow-reactor, utilising an electrochemically-generated hydrogen source to produce a mixed hydrogen-liquid flow stream.

A highly automated, polymer-assisted strategy for the preparation of 2-alkylthiobenzimidazoles and N,N'-dialkylbenzimidazolin-2-ones.

A multistep, polymer-assisted solution phase strategy for the highly automated (auto-PASP) synthesis of 2-alkylthiobenzimidazole and N,N'-dialkylbenzimidazolin-2-one libraries is presented. The approach incorporates in-line purification techniques to afford library products directly with high purities and is exemplified by the preparation of a 96-member 2-alkylthiobenzimidazoline library 1[1-12,1-8] and a 72-member N,N'-dialkylbenzimidazolin-2-one library 9[1-12,1-6].

Effect of chain length on transfection properties of spermine-based gemini surfactants.

The synthesis and associated structure-activity relationships for gene transfection of a series of spermine-derived cationic gemini surfactants incorporating diamino acid headgroups and either identical (symmetrical) or different (unsymmetrical) lipophilic tailgroups is described. Transfection activity is found to depend critically upon the structural elements present.

A fluorous-tagged, acid-labile protecting group for the synthesis of carboxamides and sulfonamides.

A new acid-labile, fluorous-tagged protecting group that facilitates the preparation of carboxamides and sulfonamides by parallel solution-phase synthesis is introduced. Its use is exemplified by the preparation of a 27-member library of biaryl sulfonamides and an 18-member library of biaryl carboxamides. Intermediates were purified by solid-phase extraction over reversed-phase fluorous silica gel to afford library members in high yields and purities (>95%) without the need for column chromatographic purification.

Automated flow-through synthesis of heterocyclic thioethers.

The fully automated, sequential flow-through synthesis of a 44-member array of thioethers 10[1-4,1-11] employing a resin "capture and release" reactor column is described. The array incorporates four different heterocyclic scaffolds, and the synthesis was performed using a custom-built robotic synthesizer that is able to (i) load and regenerate the reactor column and (ii) array each product into a single vial using UV threshold detection. All the compounds were obtained in high yield (>75%) and excellent purity (>95%) without the need for further purification.

Complete functionalisation of small and large diameter bromopolystyrene beads; applications for solid-supported reagents, scavengers and diversity-oriented synthesis.

Bromopolystyrene beads with diameters of up to 600 microm have been derivatized completely, via bromine-magnesium exchange and interception with electrophiles, to yield high quality solid-supported reagents, scavengers and solid supports for use in diversity-oriented synthesis.

Fully automated polymer-assisted synthesis of 1,5-biaryl pyrazoles.

The polymer-assisted solution-phase (PASP) synthesis of a 192-member 2-D array of 1,5-biaryl pyrazoles 4[1-12,1-16] is reported. The synthesis was performed in a fully automated manner using a multiprobe top-filtration robot and incorporates a "catch and release" step to afford library compounds directly in high yield and purity.

A novel phase-switching protecting group for multi-step parallel solution phase synthesis.

A new phase-tag 1 which facilitates the parallel solution phase synthesis of carboxylic acids, esters, and carboxamides is reported. The new phase tag assists compound purification by enabling the selective resin capture of reaction products in either a reversible pH dependent manner (solid-phase extraction), or irreversibly in a Diels-Alder reaction.

Automated parallel, multi-step polymer-assisted solution phase (PASP) synthesis of substituted benzimidazole derivatives.

The automated polymer-assisted solution phase (PASP) synthesis of a 72 member library of 2-alkylthio-benzimidazoles 16 and benzimidazolin-2-ones 17 using commercially available robotic workstations is described. By incorporating both automated aqueous work-ups, in-line scavenging and 'catch and release' protocols the desired compounds were obtained directly in good yields and excellent purities without the need for conventional chromatographic purification. The synthesis described demonstrates how both manual and automated equipment may be utilised together to provide a versatile approach that facilitates parallel compound synthesis.

Polymer-assisted, multi-step solution phase synthesis and biological screening of histone deacetylase inhibitors.

The polymer-assisted solution phase synthesis (PASP) of an array of histone deacetylase (HDAc) inhibitors is described. HDAc inhibitors have considerable potential as new anti-proliferative agents. Selected compounds were shown to inhibit both human endothelial cell proliferation, and the formation of tubules (neovascularisation) in an in vitro model of angiogenesis.

Polymer-assisted solution phase synthesis of the antihyperglycemic agent Rosiglitazone (Avandia).

The commercially important antihyperglycemic agent Rosiglitazone 1(Avandia) has been prepared in high purity by a multi-step, polymer-assisted solution phase (PASP) synthesis without the need for the conventional chromatographic purification of any intermediates.

Fully automated multi-step solution phase synthesis using polymer supported reagents: preparation of histone deacetylase inhibitors.

The first fully automated multi-step polymer assisted solution phase (PASP) synthesis is described. An array of histone deacetylase (HDAc) inhibitors was prepared by an unattended 4-5 step sequence incorporating in-line 'catch and release' purification.

Wavelength dependent photo-controlled differential release of compounds from solid phase resin.

A method to effect photo-mediated differential release of bead-based compound libraries using a tuneable laser in combination with chromatically orthogonal photolabile linkers is described.

The development and preparation of the 2,4-dimethoxybenzyl arylhydrazine (DMBAH) "latent" safety-catch linker: solid phase synthesis of ketopiperazines.

The development and preparation of the 2,4-dimethoxybenzyl arylhydrazine (DMBAH) linker 3, a new class of "latent" safety-catch linker which is stable under Mitsunobu alkylation conditions and in the presence of amines and hydrazine, is reported. The utility of the new linker is exemplified by the synthesis of ketopiperazines (MKPs) 24 bearing up to four points of diversity using a cyclitive cleavage approach.

Convenient preparation and use of a new analytical construct for the analysis and development of solid-phase chemistries.

An expedient and scalable synthesis of a versatile new analytical construct intermediate 1 is described. The utility of the intermediate 1 is exemplified by the preparation of the construct resin 14 incorporating an acid-labile linker which is used to conveniently develop optimized conditions leading to the preparation of a small compound array 24(1-3,1-3). The optimized conditions are shown to work equally well on both the construct resin 14 and the corresponding base resin 15.

A novel anthracenyl tagged protecting group for "phase-switching" applications in parallel synthesis.

A new "phase-switching" protecting group 1 that facilitates the parallel synthesis of carboxylic acids, esters, and carboxamides is described. Its use permits chemistries to be performed in solution, which may be conveniently monitored with conventional analytical techniques, followed by subsequent immobilization onto a solid-phase support to aid compound purification. Carboxylic acids, esters, and carboxamides are then cleaved from the solid support following activation of the "safety-catch" and treatment with the desired nucleophile.