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

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.publishedVersionPeer reviewe

Lewis Base-Catalyzed Modification of Ortho-Substituted Phenols

Lewis base catalysis in chemical transformations has received tremendous recognition in both academic and industrial applications over the years as it offers a convenient alternative to the use of expensive/toxic metal or large enzyme catalysts under mild reaction conditions. In light of this, efforts towards the development of synthetic strategies that employ Lewis base catalysts in mild and selective organic transformations are highly desirable. In this thesis, we present an efficient Lewis base promoted hydrosilylation protocol with a novel cyclic 5-membered pinacol-derived chlorohydrosilane (PCS). This study provides information on the reactivity of this chlorohydrosilane as a hydride donor in the reduction of carbonyl and C=N moieties. Screening of various Lewis bases led to identification of DMPU as an effective catalyst for the hydrosilylation of salicylaldehydes. The role of the base as a catalyst in the reaction mechanism is further supported by computational studies. Hydroquinone serves as a starting material for the synthesis of formyl-hydroquinone, which was used to test the efficiency of our hydrosilylation protocol. The synthesis of hydroquinone from naturally available quinic acid was also studied. The hydrosilylation method was further developed for the preparation of novel tertiary alkylphenolmethyl amines employing pyridine as an effective Lewis base catalyst. During the course of the study, the unprecedented preparation of 6, 12disubstituted methanodibenzo[b,f][1,5]dioxocins from pyrrolidine-catalyzed selfcondensation of 2’-hydroxyacetophenones was discovered and improved. This fascinating highly bridged polycyclic core is present in numerous biologically active natural products and pharmaceuticals. The findings presented in this thesis exemplifies the high reactivity of PCS as a new reagent for Lewis base-catalyzed hydrosilylation. It is nevertheless envisioned that this silane finds usefulness in the hydrosilylation of other functional groups besides those employed in this work. In addition, the study provides mild and selective synthetic strategies to access diverse phenolic compounds of potential use by the pharmaceutical industry in the development of new bioactive molecules

Pinacol-Derived Chlorohydrosilane in Metal-Free Reductive Amination for the Preparation of Tertiary Alkylphenolmethyl Amines

A new metal-free reductive amination protocol using a pinacol-derived chlorohydrosilane/pyridine system for the preparation of aminoalkylphenols is described. This method is selective toward iminiums derived from alkylphenol ketones under an in situ formation of a trialkoxyhydrosilane and activation with a Lewis base, as further indicated by computational studies. This method demonstrated high functional group tolerance affording an array of novel aminoalkylphenols in moderate to high yields with equimolar amounts of reactants and a wide substrate scope.publishedVersionPeer reviewe

Biomass-Based and Oxidant-Free Preparation of Hydroquinone from Quinic Acid

A biomass-based route to the preparation of hydroquinone starting from the renewable starting material quinic acid is described. Amberlyst-15 in the dry form promoted the one-step formation of hydroquinone from quinic acid in toluene without any oxidants or metal catalysts in 72 % yield. Several acidic polymer-based resins and organic acids as promoters as well as a variety of reaction conditions were screened including temperature, concentration and low- and high-boiling-point solvents. A 1:4 (w/w) ratio of quinic acid/Amberlyst-15 was determined to be optimal to promote hydroquinone formation with only traces of a dimeric side-product. A mechanism has been proposed based on the decarbonylation of protonated quino-1,5-lactone that is supported by experimental and computational calculation data.submittedVersionPeer reviewe

Synthesis of 6,12-Disubstituted Methanodibenzo[b,f][1,5]dioxocins : Pyrrolidine Catalyzed Self-Condensation of 2′-Hydroxyacetophenones

The preparation of unprecedented 6,12-disubstituted methanodibenzo[b,f][1,5]dioxocins from pyrrolidine catalyzed self-condensation of 2′-hydroxyacetophenones is herein described. This method provides easy access to this highly bridged complex core, resulting in construction of two C–O and two C–C bonds, a methylene bridge and two quaternary centers in a single step. The intricate methanodibenzo[b,f][1,5]dioxocin compounds were obtained in up to moderate yields after optimization of the reaction conditions concerning solvent, reaction times and the use of additives. Several halide substituted methanodibenzo[b,f][1,5]dioxocins could be prepared from correspondent 2′-hydroxyacetophenones.peerReviewe

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

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