Synthesis of Novel Benzofuran Spiro-2-Pyrrolidine Derivatives via [3+2] Azomethine Ylide Cycloadditions and Their Antitumor Activity

A synthetic strategy of a three-component spiro-pyrrolidine compound based on benzofuran via an [3+2] azomethine ylide cycloaddition reaction is reported herein. Under mild optimal conditions, this reaction can quickly produce potentially bioactive compounds with a wide range of substrates, high yield, and simple operation. The desired products were obtained with a yield of 74-99% and a diastereomeric ratio (dr) of >20:1. Subsequently, the inhibitory effects of the compounds on the cell viability of the human cancer cell line HeLa and mouse cancer cell line CT26 were evaluated. Compounds <b>4b</b> (IC₅₀ = 15.14 ± 1.33 µM) and <b>4c</b> (IC₅₀ = 10.26 ± 0.87 µM) showed higher antiproliferative activities against HeLa cells than cisplatin (IC₅₀ = 15.91 ± 1.09 µM); compounds <b>4e</b> (IC₅₀ = 8.31 ± 0.64 µM) and <b>4s</b> (IC₅₀ = 5.28 ± 0.72 µM) exhibited better inhibitory activities against CT26 cells than cisplatin (IC₅₀ = 10.27 ± 0.71 µM). The introduction of electron-donating substituents was beneficial to the inhibitory activities against cancer cells. Molecular docking simulations revealed that <b>4e</b> and <b>4s</b> may exert corresponding bioactivities by binding to antitumor targets through hydrogen bonds, providing a new approach for discovering spiro-heterocyclic antitumor drugs.