Structure-Based Design of Ultrapotent Tricyclic Ligands for FK506-Binding proteins.

Access to small, rigid, and sp3-rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506-binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate-mimicking tricyclic scaffold that precisely position functional groups for interacting with FKBPs. This was enabled by a 14-step gram-scale synthesis featuring anodic oxidation, stereospecific vinylation, and N-acyl iminium cyclization. Structure-based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date.

Inhibition of the Decomposition Pathways of Ruthenium Olefin Metathesis Catalysts: Development of Highly Efficient Catalysts for Ethenolysis.

Ruthenium-based Hoveyda-type olefin metathesis catalysts bearing novel rigid spirocyclic alkyl amino carbenes (CAACs) have been developed. They are characterized by exceptional stability toward decomposition through ß-elimination and bimolecular pathways, thus enabling unprecedented efficiency in the cross-metathesis of seed oil-derived fatty acid esters with ethylene (ethenolysis). Catalyst loading as low as 100 ppb was applied to the ethenolysis of the model substrate methyl oleate, leading to a remarkable turnover number (TON) of 2.6 million, significantly higher than previously reported (TON 340 000 at 1 ppm and 744 000 at 0.5 ppm catalyst loading). Ethenolysis of methyl esters derived from high oleic sunflower oil and rapeseed oil, readily available on an industrial scale, inexpensive, and renewable feedstocks, was for the first time effectively carried out with 0.5 ppm catalyst loading with TON as high as 964 000.

[4.3.1]Bicyclic FKBP Ligands Inhibit Legionella Pneumophila Infection by LpMip-Dependent and LpMip-Independent Mechanisms.

Legionella pneumophila is the causative agent of Legionnaires' disease, a serious form of pneumonia. Its macrophage infectivity potentiator (Mip), a member of a highly conserved family of FK506-binding proteins (FKBPs), plays a major role in the proliferation of the gram-negative bacterium in host organisms. In this work, we test our library of >1000 FKBP-focused ligands for inhibition of LpMip. The [4.3.1]-bicyclic sulfonamide turned out as a highly preferred scaffold and provided the most potent LpMip inhibitors known so far. Selected compounds were non-toxic to human cells, displayed antibacterial activity and block bacterial proliferation in cellular infection-assays as well as infectivity in human lung tissue explants. The results confirm [4.3.1]-bicyclic sulfonamides as anti-legionellal agents, although their anti-infective properties cannot be explained by inhibition of LpMip alone.

Med Chem Remote: The Frontiers in Medicinal Chemistry 2021.

Digital, but delicious! The Frontiers in Medicinal Chemistry 2021 meeting, originally intended to take place in Darmstadt, carried on as an online event from March 8-10 this year. Even with pandemic restrictions, the event co-presented by the Medicinal Chemistry Division of the German Chemical Society (GDCh), the German Pharmaceutical Society (DPhG), and the Swiss Chemical Society (SCS) proved to be a success, showcasing excellent speakers and facilitating participant interaction in an ingenious virtual setting. Over 350 participants from more than 10 countries gathered to discuss the latest trends and directions in medicinal chemistry, with sessions on molecular glues, covalent fragments, transient binding pockets and more. This report presents a summary of the key lectures and activities at the event.