Inhibition mechanisms of four ellagitannins from terminalia chebula fruits on acetylcholinesterase by inhibition kinetics, spectroscopy and molecular docking analyses.

Acetylcholinesterase (AChE) is an important therapeutic target for the treatment of Alzheimer's disease (AD), and the development of natural AChE inhibitors as candidates has played a significant role in drug discovery. In this study, the inhibition mechanisms of four ellagitannins, punicalagin, chebulinic acid, geraniin and corilagin, from Terminalia chebula fruits on AChE were investigated systematically by a combination of inhibition kinetics, multi-spectroscopic methods and molecular docking. The kinetic results showed that punicalagin, chebulinic acid and geraniin exhibited strong reversible inhibitory effects on AChE in an uncompetitive manner with the IC50 values of 0.43, 0.50, and 0.51 mM, respectively, while corilagin inhibited AChE activity in a mixed type with the IC50 value of 0.72 mM. The results of fluorescence and UV-vis spectra and fluorescence resonance energy transfer (FRET) revealed that four ellagitannins could significantly quenched the intrinsic fluorescence of AChE though a static quenching along with non-radiative energy transfer. Thermodynamic analyses showed that values of ΔG, ΔH and ΔS were negative, indicating that all binding processes were spontaneous, and the hydrogen bonding and Van der Waals forces might make a great contribution to the formation of inhibitor-AChE complexes. The synchronous fluorescence, three-dimensional (3D) fluorescence, UV-vis, and FT-IR spectra studies suggested that four ellagitannins could lead to alterations in the micro-environment and secondary structure of AChE, and thus the conformational change of AChE. Moreover, molecular docking demonstrated that four ellagitannins could interacted with main amino acid residues of AChE with affinity energies ranging from -9.9 to -8.7 kJ/mol, and further confirmed the above experimental results. This study provided valuable findings for the potential application of four ellagitannins as promising candidates in the exploration of natural AChE inhibitors for the treatment of AD.

Rh(III)-catalyzed [3 + 3] spirocyclization of 3-aryl-3-hydroxyisoindolinones with vinylene carbonate as a three-atom unit.

A [3 + 3] annulation of 3-aryl-3-hydroxyisoindolinones for the efficient synthesis of isoindolinone-derived spiroisochromenes is reported. In this Rh(III)-catalyzed spirocyclization reaction, vinylene carbonate is used as the coupling partner and acts as a three-atom synthon (C-C-O) through the decarboxylation process. This atom-economic reaction worked efficiently under mild conditions via a C-H activation pathway. It is the first example where 3-aryl-3-hydroxyisoindolinones are used as the building blocks to construct spiroheterocycles.

Synthesis of Indolo[2,1-a]benzazepinones through Rhodium-Catalyzed Cascade Reactions of 2-Arylindoles with Allyl Alcohols.

An efficient synthesis of indolo[2,1-a]benzazepinones through rhodium-catalyzed cascade reactions of 2-arylindoles with allyl alcohols has been developed. This work expands the scope of products that are available through C-H activation/intramolecular annulation reactions of 2-arylindoles in organic synthesis.