Total synthesis of myristinins A–F and 3′-hydroxy-5,7-dimethoxy-4-<i>O</i>-2′-cycloflavan by iterative generation of <i>o</i>-quinone methides

Glutamine metabolism is an important hallmark of several cancers with demonstrated antitumor activity in glioblastoma cancer cells (GBM). GBM cells regulate glutamine and use it as a major energy source for their proliferation through the glutaminolysis process. Enzymes, such as glutaminase in glutaminolysis, can be targeted by small-molecule inhibitors, thus exhibiting promising anticancer properties. The resistance to glutaminolysis demands the development of new therapeutic molecules to overcome drug resistance. Herein, we have reported a novel library of constrained methanodibenzo[b,f][1,5]dioxocin derivatives as glutaminase (GLS) inhibitors and their anti-GBM potential. The library consisting of seven molecules was obtained through self-condensation of 2′-hydroxyacetophenones, out of which three molecules, namely compounds 3, 5, and 6, were identified with higher binding energy values ranging between −10.2 and −9.8 kcal/mol with GLS (PDB ID; 4O7D). Pharmacological validation of these compounds also showed a higher growth inhibition effect in GBM cells than the standard drug temozolomide (TMZ). The most promising compound, 6, obeyed Lipinski’s rule of five and was identified to interact with key residues Arg307, Asp326, Lys328, Lys399, and Glu403 of GLS. This compound exhibited the best cytotoxic effect with IC50 values of 63 µM and 83 µM in LN229 and SNB19 cells, respectively. The potential activation of GLS by the best-constrained dibenzo[b,f][1,5]dioxocin in the tested series increased apoptosis via reactive oxygen species production in both GBM cells, and exhibited anti-migratory and anti-proliferative properties over time in both cell lines. Our results highlight the activation mechanism of a dibenzo[b,f][1,5]dioxocin from the structural basis and demonstrate that inhibition of glutaminolysis may facilitate the pharmacological intervention for GBM treatment.

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Total synthesis of myristinins A–F and 3′-hydroxy-5,7-dimethoxy-4-O-2′-cycloflavan by iterative generation of o-quinone methides

Cited by 2 publications

References 30 publications

Six-membered ring systems: With O and/or S atoms

Six-membered ring systems: With O and/or S atoms

Methanodibenzo[b,f][1,5]dioxocins as Novel Glutaminase Inhibitor with Anti-Glioblastoma Potential

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