An Unrevealed Molecular Function of Corannulene Buckybowl Glycoconjugates in Selective Tumor Annihilation by Targeting the Cancer‐Specific Warburg Effect

The biomedical application of corannulene π-bowls is historically limited by low solubility and bioavailability despite the potential in their unique electronic properties for new functional materials. Herein, the unexpected role and molecular mechanism of Corranulene π-bowls are uncovered in biomedical applications as an effective anticancer agent for Warburg effect mediated selective tumor targeting. The corannulene triazolyl monosaccharides Cor-sugars exhibit highly potent cytotoxicity against human cancer cells and effectively inhibit xenograft growth of hyperglycolytic tumors. Particularly, the galactose-conjugated Cor-gal exhibits superior in vivo anticancer efficacy in A549 tumor models with outstanding safety profile compared to doxorubicin. Moreover, the combined treatment of Cor-gal with immune checkpoint inhibitor results in an effective synergy in treating H460 human lung carcinoma. An uptake mechanism study reveals that Cor-sugars exploit tumor-specific glucose transporter glucose transporter 1 (GLUT1) for targeted cell delivery and intra-tumoral accumulation through the cancer-specific Warburg effect. Their significant anticancer activity is attributed to multiphasic DNA-binding and cell cycle alteration effects. This study uncovers new molecular properties of corannulene buckybowl and enabling their potential new applications in biomedical engineering.