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A novel graphene oxide‐catalyzed two‐component cascade reaction in an aqueous medium has been developed to synthesize indole‐fused furopyran derivatives, overcoming significant challenges in aqueous organic reactions to advance eco‐friendly chemical processes. Density functional theory (DFT) studies were conducted to clarify the mechanism and to understand the role of temperature in forming our desired kinetic controlled product (KCP). Using a pharmacophore hybrid approach, a series of indole‐fused furopyran derivatives were designed and molecular docking was performed to assess their binding affinities toward target proteins in liver and breast cancer. The derivatives exhibited strong affinities, particularly towards the 4FA6 and 1U72 proteins, driven by hydrogen bonding interactions with specific amino acid residues. Ten best derivatives which showed strong binding affinities and favorable docking scores, were synthesized using the two‐component cascade reaction in an aqueous medium and tested for in vitro activity against liver and breast cancer cells. These derivatives showed notable antiproliferative activity against cancer cell lines, with promising IC50 values against breast and hepatocellular carcinoma, highlighting its potential as an anticancer drug candidate. The most potent compounds, 4d and 4f, demonstrated significant cytotoxicity against HepG2 and MCF7 cell lines, with IC50 values of 42.36 µM and 35.69 µM, respectively. To the best of our knowledge, the anti‐cancer activity of indole‐fused furopyran derivatives is being investigated for the first time for potential therapeutic development in combating these challenging diseases. [ABSTRACT FROM AUTHOR]

A simple, highly effective synthesis of tetracyclic pyrano[3,4‐b]indoles derivatives from simple 2‐indolylmethanols and trione alkenes has been accomplished through oxa‐Michael addition‐Friedel–Crafts reaction‐cyclization cascade promoted by a cheap and green graphene oxide catalyst. Under mild conditions, the reaction afforded a range of pyrano[3,4‐b]indole scaffolds, which are an important structural unit of different bioactive molecules, in excellent yields. Most importantly, in the cascade reaction of 2‐indolylmethanols with trione alkenes, the nanocatalyst not only activates trione alkene substrates by forming hydrogen‐bonding, but also promotes the following intramolecular ring formation and dehydration. Moreover, graphene oxide showed high recyclability in this reaction and could be used in gram scale synthesis. To the best of our knowledge, graphene oxide is used for the first time in the synthesis of functionalized tetracyclic dihydropyranoindole derivatives. [ABSTRACT FROM AUTHOR]