Discovery of a Novel Pseudo-Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling.

The pseudo-natural product (pseudo-NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three-dimensional pseudo-NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B.

Structure-activity relationship studies of tetrahydroquinolone derivatives as GPR41 modulators.

GPR41, a G protein-coupled receptor, serves as a sensor for short-chain fatty acids and plays a crucial role in regulating multiple physiological processes such as the maintenance of metabolic and immune homeostasis. Therefore, the modulation of GPR41 has garnered attention as a potential strategy for the treatment of various disorders. We conducted a structure-activity relationship study on a lead tetrahydroquinolone derivative bearing a 2-(trifluoromethoxy)benzene group that displayed antagonistic activity toward GPR41. Modification of the aryl group attached to the furan moiety revealed that derivatives containing di- or trifluorobenzene, instead of 2-(trifluoromethoxy)benzene, exhibited agonistic activity toward GPR41, comparable with the reported agonistic modulator AR420626. These results suggest that the aryl group plays a pivotal role in regulating the activity of compounds toward GPR41, providing valuable insights for the design of GPR41 modulators.

Gold(I)-Catalyzed Benzylic C(sp3 )-H Functionalizations: Divergent Synthesis of Indole[a]- and [b]-Fused Polycycles.

Phenyl azides substituted by an (alkylphenyl)ethynyl group facilitate benzylic sp3 (C-H) functionalization in the presence of a JohnPhosAu catalyst, resulting in indole-fused tetra- and pentacycles via divergent N- or C-cyclization. The chemoselectivity is influenced depending on the counter-anion, the electron density of the α-imino gold(I) carbene, and the alkyl groups stabilizing the benzylic carbocation originating from a 1,5-hydride shift. An isotopic labeling experiment demonstrates the involvement of an indolylgold(I) species resulting from a tautomerization that is much faster than the deauration. The formation of a benzylic sp3 (C-H) functionalization leading to an indole-fused seven-membered ring is also demonstrated.

Fluorination of silyl prosthetic groups by fluorine mediated silyl ether linker cleavage: a concept study with conditions applicable in radiofluorination.

BACKGROUND: Positron emission tomography (PET) is a powerful tool in medical imaging, especially in combination with the PET radionuclide fluorine-18 that possesses optimal characteristics. For labelling of biomolecules and low-molecular weight tracers, fluorine-18 can be covalently bound to silicon by either nucleophilic replacements of leaving groups (like ethers) or by isotope exchange of fluorine-19. While nucleophilic substitutions require additional purification steps for the removal of contaminants, isotope exchange with fluorine-18 results in low molar activity. Both challenges can be addressed with a detagging-fluorination of an immobilized silyl ether motif. RESULTS: By overcoming the susceptibility towards hydrolysis, optimized detagging conditions (improved reaction time, fluorination reagent, linker, and resin) could afford the highly sterically hindered silyl fluoride motifs, that are commonly applied in radiochemistry in small and semipreparative scales. The described reaction conditions with fluorine-19 are transferrable to conditions with [18F]fluoride and silyl fluorides were obtained after approx. 10 min reaction time and in high-purity after mechanical filtration. CONCLUSIONS: We present a proof-of-concept study for a detagging-fluorination of two silyl ethers that are bound to an optimized amino alcohol resin. We show with our model substrate that our solid-phase linker combination is capable of yielding the desired silicon fluoride in amounts sufficient for biological studies in animals or humans under standard fluorination conditions that may also be transferred to a radiolabelling setting. In conclusion, our presented approach could optimize the molar activity and simplify the preparation of radiofluorinated silyl fluorides.

Azido-Alkynes in Gold(I)-Catalyzed Indole Syntheses.

The exploitation of nitrogen-functionalized reactive intermediates plays an important role in the synthesis of biologically relevant scaffolds in the field of pharmaceutical sciences. Those based on gold carbenes carry a strong potential for the design of highly efficient cascade processes toward the synthesis of compounds containing a fused indole core structure. This personal account gives a detailed explanation of our contribution to this sector, and embraces the reaction development of efficient gold-catalyzed cascade processes based on diversely functionalized azido-alkynes. Challenging cyclizations and their subsequent application in the synthesis of pharmaceutically relevant scaffolds and natural products conducted in an intra- or intermolecular fashion are key features of our research.

Access to Indole-Fused Benzannulated Medium-Sized Rings through a Gold(I)-Catalyzed Cascade Cyclization of Azido-Alkynes.

Invited for the cover of this issue is Hiroaki Ohno and co-workers at Kyoto University, Hokkaido University, and Heidelberg University. The image depicts a golden compass that guides the adventurer's way in an unknown chemical space. Read the full text of the article at 10.1002/chem.202101824.

"Golden" Cascade Cyclization to Benzo[c]-Phenanthridines.

Herein, we describe a gold-catalyzed cascade cyclization of Boc-protected benzylamines bearing two tethered alkyne moieties in a domino reaction initiated by a 6-endo-dig cyclization. The reaction was screened intensively, and the scope was explored, resulting in nine new Boc-protected dihydrobenzo[c]phenanthridines with yields of up to 98 %; even a π-extension and two bidirectional approaches were successful. Furthermore, thermal cleavage of the Boc group and subsequent oxidation gave substituted benzo[c]phenanthridines in up to quantitative yields. Two bidirectional approaches under the optimized conditions were successful, and the resulting π-extended molecules were tested as organic semiconductors in organic thin-film transistors.

Access to Indole-Fused Benzannulated Medium-Sized Rings through a Gold(I)-Catalyzed Cascade Cyclization of Azido-Alkynes.

Because benzannulated and indole-fused medium-sized rings are found in many bioactive compounds, combining these fragments might lead to unexplored areas of biologically relevant and uncovered chemical space. Herein is shown that α-imino gold carbene chemistry can play an important role in solving the difficulty in the formation of medium-sized rings. Namely, phenylene-tethered azido-alkynes undergo arylative cyclization through the formation of a gold carbene intermediate to afford benzannulated indole-fused medium-sized tetracycles. The reactions allow a range of different aryl substitution patterns and efficient access to these otherwise difficult-to-obtain medium-sized rings. This study also demonstrates the feasibility of the semihollow-shaped C-dtbm ligand for the construction of a nine-membered ring.