Discovery of a small-molecule binder of the oncoprotein gankyrin that modulates gankyrin activity in the cell.

Gankyrin is an ankyrin-repeat oncoprotein whose overexpression has been implicated in the development of many cancer types. Elevated gankyrin levels are linked to aberrant cellular events including enhanced degradation of tumour suppressor protein p53, and inhibition of gankyrin activity has therefore been identified as an attractive anticancer strategy. Gankyrin interacts with several partner proteins, and a number of these protein-protein interactions (PPIs) are of relevance to cancer.

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis.

The synthesis of diverse three-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis.

Palladium-catalysed cross-coupling of vinyldisiloxanes with benzylic and allylic halides and sulfonates.

The Hiyama cross-coupling reaction is a powerful method for carbon-carbon bond formation. To date, the substrate scope of this reaction has predominantly been limited to sp(2)-sp(2) coupling reactions. Herein, the palladium-catalysed Hiyama type cross-coupling of vinyldisiloxanes with benzylic and allylic bromides, chlorides, tosylates and mesylates is reported.

Diversity-oriented synthesis: producing chemical tools for dissecting biology.

Small molecule modulators of biological function can be discovered by the screening of compound libraries. However, it became apparent that some human disease related targets could not be addressed by the libraries commonly used which typically are comprised of large numbers of structurally similar compounds. The last decade has seen a paradigm shift in library construction, with particular emphasis now being placed on increasing a library's structural, and thus functional diversity, rather than only its size.

Synthesis and biological profiling of tellimagrandin I and analogues reveals that the medium ring can significantly modulate biological activity.

A novel synthesis of the ellagitannin natural product tellimagrandin I and a series of medium ring analogues is described. These compounds were all subsequently screened for redox activity, ability to precipitate protein and cellular phenotype in HeLa cells. From this we have shown that all properties can be modulated independently by varying ring size and by moving the ester out of conjugation with the biaryl ring system.

Chemical genetics.

Chemical genetics can be defined as the study of biological systems using small molecule tools. Cell permeable and selective small molecules modulate gene product function rapidly, reversibly and can be administered conditionally in either a cellular or organismal context. The small molecule approach provides exacting temporal and quantitative control and is therefore an extremely powerful tool for dissecting biological processes.

Synergistic organocatalysis in the kinetic resolution of secondary thiols with concomitant desymmetrization of an anhydride.

Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Thiols are precursors to a variety of organosulfur compounds, with high utility in both chemistry and chemical biology, yet there is a surprising dearth of methodologies for their direct and efficient catalytic kinetic resolution. Here, we demonstrate an organocatalytic process involving the highly enantioselective desymmetrization of an achiral electrophile with the simultaneous kinetic resolution of a racemic thiol.

Facile synthesis of 3-nitro-2-substituted thiophenes.

A new approach to 3-nitro-2-substituted thiophenes has been developed. Exposure of commercially available 1,4-dithane-2,5-diol to nitroalkenes in the presence of 20% triethylamine results in a tandem Michael-intramolecular Henry reaction to form the corresponding tetrahydrothiophene. Subsequent microwave irradiation on acidic alumina in the presence of chloranil effects the solvent free dehydration and aromatization to form 3-nitro-2-substituted thiophenes cleanly and rapidly.

Glottic insertion of the ProSeal LMA occurs in 6% of cases: a review of 627 patients.

Purpose: Glottic insertion of the ProSeal Laryngeal Mask Airway (PLMA) has received little attention in the anesthesiology literature. We investigated the incidence and depth of insertion associated with this important cause for a failed insertion attempt with the PLMA.

Methods: With Institutional Review Board approval, we reviewed 15-months' use of the PLMA.

Maximum minute ventilation test for the ProSeal laryngeal mask airway.

Unlabelled: One of the distinguishing features of the ProSeal laryngeal mask airway (PLMA) is that it can cause upper airway obstruction, even when it is correctly inserted behind the cricoid cartilage. We used a hyperventilation test, the maximum minute ventilation test (MMV test), to aid in the diagnosis of upper airway obstruction after PLMA insertion. The patient was briefly hyperventilated for 15 s yielding a MMV value equal to 4 x (breaths/15 s) x (exhaled tidal volume).

Gastric distention in a spontaneously ventilating patient with a ProSeal laryngeal mask airway.

Partial upper airway obstruction during spontaneous respiration with a ProSeal laryngeal mask airway can result in gastric distention.

Esophageal insufflation with normal fiberoptic positioning of the ProSeal laryngeal mask airway.

Esophageal insufflation can occur simultaneously with venting from the drain tube during positive pressure ventilation with the ProSeal laryngeal mask airway.