Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles

Oxindoles and iso-oxindoles are natural product-derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso-oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective Rh^III-catalyzed scaffold-divergent synthesis of spirooxindole–isooxindoles and spirooxindole–oxindoles from differently protected diazooxindoles and N-pivaloyloxy aryl amides which includes a functional group-controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.     

Heteroleptic Copper(I)-Based Complexes Incorporating BINAP and π-Extended Diimines: Synthesis,Catalysis and Biological Applications

A series of copper-based photocatalysts of the type Cu(NN)(BINAP)BF₄ were synthesized bearing π-extended diimine ligands. Their behavior in several photocatalytic processes were evaluated and revealed acceptable levels of activity in an SET process, but negligible activity in PCET or ET processes. Suitable activity in ET processes could be restored through modification of the ligand. The BINAP-derived complexes were then evaluated for activity against triple-negative breast cancer cell lines. Controls indicated that copper complexes, and not their ligands, were responsible for activity. Encouraging activity was displayed by a homoleptic complex Cu(dppz)₂BF₄.     

Specific Versus Non-specific Response in Exponential Molecular Amplification from Cross-Catalysis: Modeling the Influence of Background Amplifications on the Analytical Performances

Molecule based signal amplifications relying on an autocatalytic process may represent an ideal strategy for the development of ultrasensitive analytical or bioanalytical assays, the main reason being the exponential nature of the amplification. However, to take full advantage of such amplification rates, high stability of the starting co-reactants is required in order to avoid any undesirable background amplification. Here, on the basis of a simple kinetic model of cross-catalysis including a certain degree of intrinsic instability of co-reactants, we highlight the key parameters governing the analytical response of the system and discuss the analytical performances that are expected from a given kinetic set. In particular, we show how the detection limit is directly related to the relative instability of reactants within each catalytic loop. The model is validated with an experimental dataset and is intended to serve as a guide in the design and optimization of autocatalytic molecular-based amplification systems with improved analytical performances.     

Photocatalyzed Synthesis of 3-Substituted Phthalides: A Key Access to (±)-Herbaric Acid

An efficient organophotocatalyzed protocol was developed for the preparation of 3-substituted phthalides. The presented transformation was performed under particularly mild conditions within 6 h and was ultimately applied to a precursor of the herbaric acid.     

Kinetic Delay in Cooperative Supramolecular Polymerization by Redefining the Trade-Off Relationship between H-Bonds and Van der Waals/π–π Stacking Interactions

We here present how rebalancing the interplay between H-bonds and dispersive forces (Van der Waals/π–π stacking) may induce or not the generation of kinetic metastable states. In particular, we show that extending the aromatic content and favouring the interchain VdW interactions causes a delay into the cooperative supramolecular polymerization of a new family of toluene bis-amide derivatives by trapping the metastable inactive state.     

Late-Stage Aryl C−H Bond Cyclopropenylation with Cyclopropenium Cations

Herein, we disclose the first regio-, site- and chemoselective late-stage (hetero)aryl C−H bond cyclopropenylation with cyclopropenium cations (CPCs). The process is fast, operationally simple and shows an excellent functional group tolerance in densely-functionalized drug molecules, natural products, agrochemicals and fluorescent dyes. Moreover, we discovered that the installation of the cyclopropene ring in drug molecules could not only be used to shield against metabolic instability but also as a synthetic tool to reach medicinally-relevant sp³-rich scaffolds exploiting the highly-strained nature of the cyclopropene ring with known transformations.