Combined morphological and proteome profiling reveals target-independent impairment of cholesterol homeostasis.

Unbiased profiling approaches are powerful tools for small-molecule target or mode-of-action deconvolution as they generate a holistic view of the bioactivity space. This is particularly important for non-protein targets that are difficult to identify with commonly applied target identification methods. Thereby, unbiased profiling can enable identification of novel bioactivity even for annotated compounds.

A Scaffold-Diversity Synthesis of Biologically Intriguing Cyclic Sulfonamides.

A "branching-folding" synthetic strategy that affords a range of diverse cyclic benzo-sulfonamide scaffolds is presented. Whereas different annulation reactions on common ketimine substrates build the branching phase of the scaffold synthesis, a common hydrogenative ring-expansion method, facilitated by an increase of the ring-strain during the branching phase, led to sulfonamides bearing medium-sized rings in a folding pathway. Cell painting assay was successfully employed to identify tubulin targeting sulfonamides as novel mitotic inhibitors.

Scaffold Diversity Synthesis Delivers Complex, Structurally, and Functionally Distinct Tetracyclic Benzopyrones.

Complexity-generating chemical transformations that afford novel molecular scaffolds enriched in character are highly desired. Here, we present a highly stereoselective scaffold diversity synthesis approach that utilizes cascade double-annulation reactions of diverse pairs of zwitterionic and non-zwitterionic partners with 3-formylchromones to generate highly complex tetracyclic benzopyrones. Each pair of annulation partners adds to the common chroman-4-one scaffold to build two new rings, supporting up to four contiguous chiral centers that include an all-carbon quaternary center.

Engaging Allene-Derived Zwitterions in an Unprecedented Mode of Asymmetric [3+2]-Annulation Reaction.

Catalytic addition of chiral phosphine, that is, (R)- or (S)-SITCP, to an α-substituted allene ester generated a zwitterionic dipole. Under optimized reaction conditions, this dipole could engage isatine-derived N-Boc-ketimines in a novel mode of [3+2] annulation reaction. Pyrrolinyl spirooxindoles are thus afforded in high yields and with excellent enantioselectivities.

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery.

Scaffold diversity is a crucial feature of compound collections that has a huge impact on their success in biological screenings. The synthesis of highly complex and diverse scaffolds, which could be based on natural products, for example, is an arduous task that requires expertise in various aspects of organic synthesis and structural analysis. This challenge has been addressed by a number of synthesis designs, which employ natural products as a source of scaffold diversity, transform suitably designed common intermediates into various molecular frameworks, or entail highly concise synthetic routes to a number of distinct and complex scaffolds.

Stereoselective synthesis of a natural product inspired tetrahydroindolo[2,3-a]-quinolizine compound library.

A natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3-a]quinolizine scaffold was established with a five step synthesis route. An imino-Diels-Alder reaction between Danishefsky's diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold.

Regioselective reductive cleavage of bis-benzylidene acetal: stereoselective synthesis of anticancer agent OGT2378 and glycosidase inhibitor 1,4-dideoxy-1,4-imino-l-xylitol.

A highly regioselective reductive cleavage of the bis-benzylidene acetal of D-mannitol was performed using a BF(3) x Et(2)O/Et(3)SiH reagent system. A chiral intermediate 6 thus obtained was efficiently utilized in the stereoselective synthesis of the anticancer agent OGT2378 (3) and glycosidase inhibitor derivative N-tosyl 1,4-dideoxy-1,4-imino-L-xylitol (22). Chemoselective reduction of azido epoxide 10 followed by regioselective intramolecular cyclization of amino epoxide 11 resulted in the exclusive formation of deoxyidonojirimycin derivative 12.