Christopher J. Northfield

Discovery of Cell-Active Phenyl-Imidazole Pin1 Inhibitors by Structure-Guided Fragment Evolution.

Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-μM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential.

A facile and highly stereoselective approach to a polycyclic isoindolinone ring system via an N-acyliminium ion cyclization reaction

A highly diastereoselective synthesis of chiral ring-fused isoindolinone products, the skeleton of which is common to many naturally occurring and biologically active compounds, is achieved in only two synthetic steps from readily available precursors via an N-acyliminium ion cyclization reaction of an isoindolinone substrate.

A highly diastereoselective synthesis of tricyclic lactams and their application as novel N-acyl iminium ion precursors in the synthesis of isoindolinone derivatives

Condensation of 2-formylbenzoic acid with α-amino alcohol substrates proceeds with extremely high diastereoselectivity to produce tricyclic γ-lactam products. The relative stereochemistry of the major diastereoisomer has been determined by X-ray crystal analysis and a mechanism suggested to explain the stereochemical outcome. Further, we report that this class of heterocycle can act as an N-acyl iminium ion precursor in the synthesis of substituted isoindolinone derivatives.

Synthesis and antimicrobial activity of some isoindolin-1-ones derivatives

A range of N-substituted isoindolin-1-ones was prepared and their potential as novel antimicrobial agents was investigated. MIC values for active compounds were determined and reported.

A highly diastereoselective synthesis of 3-substituted isoindolin-1-one dericatives

A highly diastereoselective method for the synthesis of 3-substituted isoindolin-1-ones has been developed through application of a tricyclic lactam substrate as an N-acyliminium ion precursor. Ring-opening of the tricyclic lactam with triethylsilane as hydride source generates the targets with up to exclusive levels of diastereoselectivity. This approach compliments that reported in the preceding paper.

A new approach to the synthesis of non-racemic isoindolin-1-one derivatives

A new approach for the synthesis of non-racemic 3-substituted isoindolin-1-one targets has been developed through application of a tricyclic γ-lactam substrate as an N-acyliminium ion precursor.

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.

Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.

Approaches to the synthesis of non-racemic 3-substituted isoindolinone derivatives

New methodology for the synthesis of non-racemic isoindolinone targets has been developed through application of tricyclic γ-lactam substrates as N-acyliminium ion precursors in reactions with carbon and hydride nucleophiles. Removal of the phenylglycinol derived chiral auxiliary can be achieved without loss of stereochemical integrity at the newly created asymmetric centre, and we report a novel method for this key step using conc. sulfuric acid.