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

Abstract

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.

Supramolecular Chemistry of Sumanene

“…[43][44][45] As for now in buckybowl science, mostly corannulene derivatives were recently used in medicinal chemistry, showing great potential of buckybowls toward treatments in humans. [46,47] Several theoretical works on the application of sumanene buckybowl in drug delivery were published very recently (2022-2023). [48][49][50] These works were based on the density functional theory (DFT) computations on various models comprising drugs, and sumanene molecule.…”

Galactose: A Versatile Vector Unveiling the Potentials in Drug Delivery, Diagnostics, and Theranostics

“…Liu et al have investigated a new category of anti-cancer agents called corranulene monoglycoconjugates (Cor-sugars, Figure 16 ) [ 67 ]. They explored various aspects of these compounds, including their synthesis, cytotoxicity, effectiveness in vivo, molecular uptake, and distinctive mechanisms for targeting tumors.…”

Oxidation-derived anticancer potential of sumanene–ferrocene conjugates

“…The reports only include corannulene derivatives as cholera toxin inhibitors 34 and click chemistry derived corannulene glycoconjugates as cancer-specific molecules. 35 The potential biological behaviors of sumanene derivatives only include recent (2021–2023) theoretical studies 36,37 on the prospective use of sumanene molecules in drug delivery. Interestingly, in these computational works, the bowl-to-bowl inversion property of sumanene molecules was considered as the driving force towards the design of effective drug delivery systems.…”