Design, Synthesis, and Biological Evaluation of Tetrahydro‐α‐carbolines as Akt1 Inhibitors That Inhibit Colorectal Cancer Cell Proliferation

Abstract

A series of densely functionalized THαCs were designed and synthesized as Akt1 inhibitors. Organocatalytic [3 + 3] annulation between indolin-2-imines 1 and nitroallylic acetates 2 provided rapid access to this pharmacologically interesting framework. In vitro kinase inhibitory abilities and cytotoxicity assays revealed that compound 3 af [(3S*,4S*)-4-(4-bromo-2fluorophenyl)-9-methyl-3-nitro-1-tosyl-2,3,4,9-tetrahydro-1Hpyrido[2,3-b]indole] was the most potent Akt1 inhibitor, and mechanistic study indicated that compound 3 af suppressed the proliferation of colorectal cancer cells via inducing apoptosis and autophagy. Molecular docking suggested that the indole fragment of 3 af was inserted into the hydrophobic pocket of Akt1 protein, and the H-bond between 3 af and residue Lys179 also contributed to the stable binding. This article provides an efficient strategy to design and synthesize biologically important compounds as novel Akt1 inhibitors.

Fluorinated Protein–Ligand Complexes: A Computational Perspective

“…Nevertheless, fluorine hydrogen bonds are frequently observed in protein–ligand complexes, particularly if the fluorinated ligand is a small organic molecule. Protein targets include FXIa, μ opioid receptor, YAP:TEAD protein–protein interaction, S1P receptor, Akt1, HIV protease, tyrosinase, Bruton’s tyrosine kinase, Janus kinases, and the SARS-CoV-2 main protease. − Thus, hydrogen bonds with fluorine as an acceptor are by no means a marginal phenomenon in protein–ligand systems. Whether they are a driving force for the stability of a protein–ligand complex and can thus be exploited as a design element is, however, questionable.…”