Efficient, multi-hundred-gram scale access to E3 ubiquitin ligase ligands for degrader development.

Small molecule heterobifunctional degraders (commonly also known as PROTACs) offer tremendous potential to deliver new therapeutics in areas of unmet medical need. To deliver on this promise, a new discipline directed at degrader design and optimization has emerged within medicinal chemistry to address a central challenge, namely how to optimize relatively large, heterobifunctional molecules for activity, whilst maintaining drug-like properties. This process involves simultaneous optimization of the three principle degrader components: E3 ubiquitin ligase ligand, linker, and protein of interest (POI) ligand.

Stimuli responsive asymmetric catalysis by triggered pseudo-enantiomeric proligand release.

Complex stimuli responsive systems are the basis for molecular machines and computing. A dual psuedo-enantiomer system was conceived, where the combination of two 'switch-on' asymmetric catalytic cycles could be selectively triggered to afford an enantioenriched product. Two pseudo-enantiomeric proligands were designed and synthesised for selective activation by fluoride and alkaline phosphatase.

Ratiometric Electrochemistry: Improving the Robustness, Reproducibility and Reliability of Biosensors.

Electrochemical biosensors are an increasingly attractive option for the development of a novel analyte detection method, especially when integration within a point-of-use device is the overall objective. In this context, accuracy and sensitivity are not compromised when working with opaque samples as the electrical readout signal can be directly read by a device without the need for any signal transduction. However, electrochemical detection can be susceptible to substantial signal drift and increased signal error.

Ratiometric electrochemical detection of β-galactosidase.

A novel ferrocene-based substrate for the ratiometric electrochemical detection of β-galactosidase was designed and synthesised. It was demonstrated to be an excellent electrochemical substrate for β-Gal detection with sensitivity as low as 0.1 U mL.

Ratiometric electrochemical detection of hydrogen peroxide and glucose.

Hydrogen peroxide (HO) detection is of high importance as it is a versatile (bio)marker whose detection can indicate the presence of explosives, enzyme activity and cell signalling pathways. Herein, we demonstrate the rapid and accurate ratiometric electrochemical detection of HO using disposable screen-printed electrodes through a reaction-based indicator assay. Ferrocene derivatives equipped with self-immolative linkers and boronic acid ester moieties were synthesised and tested, and, through a thorough assay optimisation, the optimum probe showed good stability, sensitivity and selectivity towards HO.

Approaches towards molecular amplification for sensing.

Diagnostic assays that rely on molecular interactions have come a long way; from initial reversible detection systems towards irreversible reaction indicator-based methods. More recently, the emergence of innovative molecular amplification methodologies has revolutionised sensing, allowing diagnostic assays to achieve ultra-low limits of detection. There have been a significant number of molecular amplification approaches developed over recent years to accommodate the wide variety of analytes that require sensitive detection.

Signal transduction and amplification through enzyme-triggered ligand release and accelerated catalysis.

Signal transduction and signal amplification are both important mechanisms used within biological signalling pathways. Inspired by this process, we have developed a signal amplification methodology that utilises the selectivity and high activity of enzymes in combination with the robustness and generality of an organometallic catalyst, achieving a hybrid biological and synthetic catalyst cascade. A proligand enzyme substrate was designed to selectively self-immolate in the presence of the enzyme to release a ligand that can bind to a metal pre-catalyst and accelerate the rate of a transfer hydrogenation reaction.

Trans-selective rhodium catalysed conjugate addition of organoboron reagents to dihydropyranones.

The selective synthesis of 2,6-trans-tetrahydropyran derivatives employing the rhodium catalysed addition of organoboron reagents to dihydropyranone templates, derived from a zinc-catalysed hetero-Diels-Alder reaction, is reported. The addition of both arylboronic acids and potassium alkenyltrifluoroborates have been accomplished in high yields using commercially-available [Rh(cod)(OH)]2 catalyst. The selective formation of the 2,6-trans-tetrahydropyran stereoisomer is consistent with a mechanism involving alkene association and carbometalation on the less hindered face of the dihydropyranone.

A novel DNA biosensor using a ferrocenyl intercalator applied to the potential detection of human population biomarkers in wastewater.

A new label-free electrochemical DNA (E-DNA) biosensor using a custom synthesized ferrocenyl (Fc) double-stranded DNA intercalator as a redox marker is presented. Single-stranded DNA (ssDNA) was co-immobilized on gold electrodes with 6-mecarpto-hexanol to control the surface density of the ssDNA probe, and hybridized with complementary DNA. The binding of the Fc intercalator to dsDNA was measured by differential pulse voltammetry.

A novel immobilization strategy for electrochemical detection of cancer biomarkers: DNA-directed immobilization of aptamer sensors for sensitive detection of prostate specific antigens.

We report on a novel strategy for DNA aptamer immobilization to develop sensitive electrochemical detection of a protein biomarker, with prostate specific antigen (PSA) as a case biomarker. Thiolated single-stranded DNA (ssDNA) was co-immobilized with 3-mercapto-1-propanol on gold electrodes, and used as a scaffold for DNA aptamer attachment through hybridization of the aptamer overhang (so-called "DNA-directed immobilization aptamer sensors", DDIAS). In the approach, the complementary DNA aptamer against PSA was assembled by the probe ssDNA onto the electrode to detect PSA; or the probe ssDNA directly hybridized with a complementary DNA aptamer/PSA complex following their pre-incubation in solution, so-called 'on-chip' and 'in-solution' methods, respectively.

Ratiometric electrochemical detection of alkaline phosphatase.

A novel ferrocene-derived substrate for the ratiometric electrochemical detection of alkaline phosphatase (ALP) was designed and synthesised. It was demonstrated to be an excellent electrochemical substrate for the ALP-labelled enzyme-linked immunosorbent assay (ELISA).

Silyl-protected dioxaborinanes: application in the Suzuki cross-coupling reaction.

The synthesis of a range of novel silyl-protected dioxaborinanes as a column- and bench-stable boron reagent were found to be advantageous to achieving good yields in palladium-catalysed cross-coupling reactions under standard conditions.