Synthesis and optimization of furano[3,2-d]pyrimidines as selective spleen tyrosine kinase (Syk) inhibitors.

A series of furano[3,2-d]pyrimidine Syk inhibitors were synthesized and optimized for their enzyme potency and selectivity versus other kinases. In addition, ADME properties were assessed and compounds were prepared with optimized profiles for in vivo experiments. Compound 23 was identified as having acceptable pharmacokinetic properties and demonstrated efficacy in a rat collagen induced arthritis model.

Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists.

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.

Construction and validation of an automated flow hydrogenation instrument for application in high-throughput organic chemistry.

This manuscript details the construction of a fully automated flow hydrogenation apparatus for use in high-throughput organic synthesis. The instrument comprises of a Bohdan robot platform coupled with a ThalesNano H-cube hydrogenator and a series of solvent valves and pumping mechanisms. Using this instrument, we have been able to fully automate a number of key transformations that could not otherwise be conveniently undertaken in a high-throughput manner.

Antibody interference with N-acyl homoserine lactone-mediated bacterial quorum sensing.

Many bacterial pathogens coordinate their virulence factor expression in a cell density-dependent manner. This population-dependent coordination of gene expression in bacteria has been termed "quorum sensing" (QS). N-Acyl homoserine lactones (AHLs) are used by over 70 Gram-negative bacterial species as autoinducers. Inhibition of QS signaling might represent a new target for antimicrobial therapy. Here we report the hapten design, synthesis, generation of monoclonal antibodies (mAbs) against AHLs, and the evaluation of these mAbs for their ability to blunt QS signaling and inhibit virulence factor expression in P. aeruginosa. The mAbs can be envisioned as a tool for future investigations into AHL-based QS, which may aid in gaining new insights into the pathogenesis of P. aeruginosa and may ultimately lead to the development of new strategies to combat bacterial diseases.

Revisiting quorum sensing: Discovery of additional chemical and biological functions for 3-oxo-N-acylhomoserine lactones.

Bacteria use small diffusible molecules to exchange information in a process called quorum sensing. An important class of autoinducers used by Gram-negative bacteria is the family of N-acylhomoserine lactones. Here, we report the discovery of a previously undescribed nonenzymatically formed product from N-(3-oxododecanoyl)-L-homoserine lactone; both the N-acylhomoserine and its novel tetramic acid degradation product, 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione, are potent antibacterial agents. Bactericidal activity was observed against all tested Gram-positive bacterial strains, whereas no toxicity was seen against Gram-negative bacteria. We propose that Pseudomonas aeruginosa utilizes this tetramic acid as an interference strategy to preclude encroachment by competing bacteria. Additionally, we have discovered that this tetramic acid binds iron with comparable affinity to known bacterial siderophores, possibly providing an unrecognized mechanism for iron solubilization. These findings merit new attention such that other previously identified autoinducers be reevaluated for additional biological functions.

Application of diazocarbonyls in the synthesis of chemical libraries.

The last few years has seen a revolution in combinatorial chemistry, an approach that has been developed for the synthesis of chemical libraries for application within the pharmaceutical industry. Many chemical methods have been investigated, which can be utilized in all manner of strategies for library synthesis, including reactions of diazocarbonyls. This review discusses the application of diazocarbonyl functionalized molecules for the preparation of chemical libraries.

N-H insertion reactions of primary ureas: the synthesis of highly substituted imidazolones and imidazoles from diazocarbonyls.

Primary ureas have been used as substrates in rhodium-catalyzed N-H insertion reactions with an array of diazocarbonyls. The insertion reaction is efficient and gives excellent selectivity and yields. The products from the insertion reaction with diazoketones cyclize readily in the presence of acid to yield the corresponding imidazolones that can be further derivatized by N-alkylation with alkyl, allyl, and benzyl halides. Alternatively, the imidazolones were treated with phosphorus oxybromide to form the corresponding 2-bromoimidazoles that were further functionalized using a Suzuki coupling reaction.

N-h insertion reactions of Boc-amino acid amides: solution- and solid-phase synthesis of pyrazinones and pyrazines.

A series of alpha-diazo-beta-ketoesters were reacted with Boc amino acid amides in the presence of rhodium octanoate catalyst. The resulting N-H insertion products were treated with acid, providing the 1,4-azine intermediates, which were oxidized by air to form the corresponding pyrazine-6-one products. The pyrazine-6-ones were further derivatized by N-alkylation or by conversion to the arylpyrazines using sequential bromination and Suzuki coupling reactions. [reaction: see text]

Smart cleavage reactions: the synthesis of an array of ureas from polymer-bound carbamates.

The solid-phase synthesis of a library of di-, tri-, and tetrasubstituted ureas is described. In this approach, an array of polymer-bound carbamates was synthesized. These polymer-bound primary and secondary amine carbamates were then treated under "smart" diversity-building cleavage conditions using a series of aluminum amide complexes to form the corresponding urea cleavage products. The crude cleavage products from this study were isolated in excellent yield and purity. To show the applicability of this strategy, a series of biaryl ureas were synthesized using sequential solid-phase Suzuki coupling and urea formation reactions.

Suspension ring-opening metathesis polymerization: the preparation of norbornene-based resins for application in organic synthesis.

A series of norbornene-based resin beads were obtained by aqueous suspension ring-opening metathesis polymerization (ROMP) and used as polymeric supports for organic synthesis. These resins were prepared from norbornene, norborn-2-ene-5-methanol, and cross-linkers such as bis(norborn-2-ene-5-methoxy)alkanes, di(norborn-2-ene-5-methyl)ether, and 1,3-di(norborn-2-ene-5-methoxy)benzene. The resulting unsaturated ROMP (U-ROMP) resins containing olefin repeat units were chemically modified using hydrogenation, hydrofluorination, chlorination, and bromination reactions to produce saturated ROMP resins with different chemical and physical properties. The hydrogenated ROMP (H-ROMP) resin was found to be highly resistant to acidic, basic, Lewis acid, and Birch reduction conditions and was assessed as a polymeric support in a series of solid-phase synthetic applications. The H-ROMP resin was found to have superior performance compared to polystyrene-divinylbenzene (PS-DVB) copolymers in aromatic nitration and acylation reactions. In a conventional five-step solid-phase synthesis of a hydantoin, similar results were obtained for both the H-ROMP and PS-DVB resins. The U-ROMP resin was also shown to be effective in the solid-phase syntheses of benzimidazoles and benzimidazolones.

Solid-phase rhodium carbenoid N-H insertion reactions: the synthesis of a diverse array of indoles.

A solid-phase synthesis of an array of indoles is reported. The key step in our approach involves a N-H insertion reaction of N-alkylanilines into a highly reactive polymer-bound rhodium carbenoid intermediate to yield the corresponding alpha-arylamino-beta-ketoester. These insertion products were then treated under acid-catalyzed cyclodehydration conditions to yield a series of polymer-bound indole esters, which were subsequently cleaved from the resin under Lewis acid-promoted amidation conditions to yield the desired indoles in good yields and with excellent purities.

Scintillation-based potassium signalling using 2,5-diphenyloxazole-tagged aza-18-crown-6.

In the presence of ionising radiation, an aza-18-crown-6 molecule covalently attached to a 2,5-diphenyloxazole (PPO) moiety scintillates weakly, addition of potassium ions results in enhanced levels of scintillation, the degree of scintillation reflecting the concentration of the potassium ions.

Rhodium carbenoid N-H insertion reactions of primary ureas: solution and solid-phase synthesis of imidazolones.

[reaction: see text] The solution and solid-phase synthesis of imidazolones is reported. The key step for the preparation of these compounds is the N-H insertion reaction of primary ureas into highly reactive rhodium carbenoid intermediates. Typically, a soluble or support-bound alpha-diazo-beta-ketoester is treated with a rhodium carboxylate catalyst in the presence of a primary urea to give the corresponding N-H insertion product. Subsequent acid-catalyzed cyclodehydration of these insertion products affords the desired imidazolone products.

Application of microgels as polymer supports for organic synthesis: preparation of a small phthalide library, a scavenger, and a borohydride reagent.

Microgel polymers containing a series of functional groups have been prepared. These microgels were composed of cross-linked poly(styrene) and were prepared by radical polymerization in solution. The microgel polymers exhibit good solubility in an array of different organic solvents, and in addition, they can be efficiently precipitated by the addition of methanol and isolated by filtration. A nine-member phthalide library was synthesized using an aminomethyl-functionalized microgel 5. To further demonstrate the versatility of these microgel polymers, tris(2-aminoethyl)amino microgel 11 was examined as a scavenger reagent to remove unreacted isocyanate after a urea synthesis. Finally, a microgel-supported ammonium borohydride reagent 14 was successfully prepared and used as a reducing agent. Notable features of these microgels are that in all applications the progress of the reaction could be monitored by standard NMR techniques and their preparation is performed using common glassware and techniques found in all organic laboratories.

Preparation of soluble and insoluble polymer supported IBX reagents.

A series of soluble and insoluble polymer supported versions of the versatile oxidizing reagent IBX has been prepared. Each of the reagents were evaluated for their efficiency in the conversion of benzyl alcohol to benzaldehyde. Results from this study were that the soluble, non-crosslinked polystyrene supported IBX reagent gave the best rate of conversion to benzaldehyde, while the macroporous polymer supported IBX resin provided a superior rate of conversion to benzaldehyde when compared with a gel type resin. The macroporous IBX reagent was also shown to convert a series of alcohols to the corresponding aldehydes and ketones.

Preparation of new microgel polymers and their application as supports in organic synthesis.

A series of soluble microgel polymers have been synthesized using solution-phase polymerization reactions. In a systematic manner, several variables such as monomer concentration, cross-linker content, reaction solvent and reaction time were examined, and this provided an optimal polymer with both solubility and precipitation characteristics suitable for synthetic applications. Thus, a chemically functionalized microgel polymer was synthesized, and the utility of this polymer in the synthesis of a small array of oxazole compounds has been demonstrated. The advantage of the microgel polymers produced was that they exhibited solution viscosities lower than those of conventional linear polymers even at higher concentrations, and this was found to be beneficial for their precipitation properties. Compounds prepared using the described microgel polymer supports were obtained in similar yields and purity when compared with insoluble resins, and more importantly, the soluble polymer bound intermediates could be analyzed at each step using standard NMR techniques.