Diastereoselective Cascade Double Michael Addition to Access Bridged Coumarins, Oxindoles and Spirooxindoles: A Sustainable Strategy for Synthesis of Anticancer Molecules.

Abstract

An efficient and concise synthesis of highly functionalized bridged coumarins has been developed through a diastereoselective double Michael addition reaction of p-quinols with various 4-hydroxy coumarins under catalyst-free conditions in H2O-DMSO (8:2). The method has been applied to oxindoles for the synthesis of a variety of bridged-oxindoles and bridged-spiroxindoles in presence of a DABCO base using H2O-EtOH (8:2) as solvent medium. The strategy is simple, highly atom economical as there is no by-product and environmentally benign (E-factor = 0.1-0.9). The synthesized compounds were screened against triple-negative breast cancers and found that bridged coumarin (3a) and oxindole (5d) compounds exhibit potent anti-cancer activity at 6.6 and 8.8 µM (IC50) concentrations respectively. Further analysis revealed that 3a and 5d caused elevated early and total apoptosis by arresting the MDA-MB-468 cells in G2/M phase of the cell cycle. Overall, our results demonstrate that bridged coumarin (3a) and oxindole (5d) compounds-based approach attenuates the cancer progression and may pave a path for the translational outcome.