From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors.

Necroptosis is a regulated caspase-independent form of necrotic cell death that results in an inflammatory phenotype. This process contributes profoundly to the pathophysiology of numerous neurodegenerative, cardiovascular, infectious, malignant, and inflammatory diseases. Receptor-interacting protein kinase 1 (RIPK1), RIPK3, and the mixed lineage kinase domain-like protein (MLKL) pseudokinase have been identified as the key components of necroptosis signaling and are the most promising targets for therapeutic intervention.

Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms.

Modulation of protein abundance using tag-Targeted Protein Degrader (tTPD) systems targeting FKBP12 (dTAGs) or HaloTag7 (HaloPROTACs) are powerful approaches for preclinical target validation. Interchanging tags and tag-targeting degraders is important to achieve efficient substrate degradation, yet limited degrader/tag pairs are available and side-by-side comparisons have not been performed. To expand the tTPD repertoire we developed catalytic NanoLuc-targeting PROTACs (NanoTACs) to hijack the CRL4 complex and degrade NanoLuc tagged substrates, enabling rapid luminescence-based degradation screening.

Late Stage Phosphotyrosine Mimetic Functionalization of Peptides Employing Metallaphotoredox Catalysis.

Access to phosphotyrosine (pTyr) mimetics requires multistep syntheses, and therefore late stage incorporation of these mimetics into peptides is not feasible. Here, we develop and employ metallaphotoredox catalysis using 4-halogenated phenylalanine to afford a variety of protected pTyr mimetics in one step. This methodology was shown to be tolerant of common protecting groups and applicable to the late stage pTyr mimetic modification of protected and unprotected peptides, and peptides of biological relevance.

Photocatalytic and Chemoselective Transfer Hydrogenation of Diarylimines in Batch and Continuous Flow.

A visible-light photocalytic method for the chemoselective transfer hydrogenation of imines in batch and continuous flow is described. The reaction utilizes EtN as both hydrogen source and single-electron donor, enabling the selective reduction of imines derived from diarylketimines containing other reducible functional groups including nitriles, halides, esters, and ketones. The dual role of EtN was confirmed by fluorescence quenching measurements, transient absorption spectroscopy, and deuterium-labeling studies.

Flow chemistry: intelligent processing of gas-liquid transformations using a tube-in-tube reactor.

CONSPECTUS: The previous decade has witnessed the expeditious uptake of flow chemistry techniques in modern synthesis laboratories, and flow-based chemistry is poised to significantly impact our approach to chemical preparation. The advantages of moving from classical batch synthesis to flow mode, in order to address the limitations of traditional approaches, particularly within the context of organic synthesis are now well established. Flow chemistry methodology has led to measurable improvements in safety and reduced energy consumption and has enabled the expansion of available reaction conditions.

The direct α-C(sp(3))-H functionalisation of N-aryl tetrahydroisoquinolines via an iron-catalysed aerobic nitro-Mannich reaction and continuous flow processing.

An efficient nitro-Mannich type direct α-C(sp(3))-H functionalisation of N-aryl-1,2,3,4-tetrahydroisoquinolines catalysed by simple iron salts in combination with O2 as the terminal oxidant is described. The use of a Teflon AF-2400 membrane Tube-in-Tube reactor under continuous flow conditions allowed for considerable process intensification to be achieved relative to previous batch methods.

Synthesis and biological evaluation of 2-anilino-4-substituted-7H-pyrrolopyrimidines as PDK1 inhibitors.

PDK1, a biological target that has attracted a large amount of attention recently, is responsible for the positive regulation of the PI3K/Akt pathway that is often activated in a large number of human cancers. A series of second-generation 2-anilino-4-substituted-7H-pyrrolopyrimidines were synthesised by installation of various functions at the 4-position of the 7H-pyrrolopyrimidine scaffold. All compounds were screened against the isolated PDK1 enzyme and dose response analysis was obtained on the best compounds of the series.

Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors.

PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald-Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines.