One-Pot Oxidative Amidation of Aldehydes via the Generation of Nitrile Imine Intermediates.

A one-pot procedure for the oxidative amidation of aldehydes via the in situ generation of reactive nitrile imine (NI) intermediates has been developed. Distinct from our progenitor processes, mechanistic and control experiments revealed that the NI undergoes rapid oxidation to an acyl diazene species, which then facilitates N-acylation of an amine. A range of substrates have been explored, including application in the synthesis of pharmaceutically relevant compounds.

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain.

The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound 7 as a weak inhibitor of the AR NTD. A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure-activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.

Computer vision as a new paradigm for monitoring of solution and solid phase peptide synthesis.

We report a strategy for the camera-enabled non-contact colourimetric reaction monitoring and optimisation of amide bond formation, mediated by coupling reagents. For amide bond formation in solution phase, investigation of reactions mediated by HATU, PyAOP, and DIC/Oxyma evidenced correlations between colour parameters extracted from video data and conversion to amide product measured by off-line HPLC analysis of concentration. These correlations, supported by mutual information analysis, were further investigated using video recordings of solid phase peptide synthesis (SPPS), co-analysed by off-line HPLC to track remaining unreacted substrate in solution. An optimisation method of coupling time in SPPS was derived from ΔE (a measurement of colour contrast), giving comparable isolated peptide yield and purity at 65-95% reduced overall reaction time. The same colour data enabled data-rich monitoring of reaction rate attenuation, consisted with computationally-derived measures of amino acid steric bulk. These findings provide a foundation for exploring the use of camera technology and computer vision towards automated and online mechanistic profiling of SPPS.