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.

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.

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.

Production and Synthetic Modifications of Shikimic Acid.

Shikimic acid is a natural product of industrial importance utilized as a precursor of the antiviral Tamiflu. It is nowadays produced in multihundred ton amounts from the extraction of star anise ( Illicium verum) or by fermentation processes. Apart from the production of Tamiflu, shikimic acid has gathered particular notoriety as its useful carbon backbone and inherent chirality provide extensive use as a versatile chiral precursor in organic synthesis. This review provides an overview of the main synthetic and microbial methods for production of shikimic acid and highlights selected methods for isolation from available plant sources. Furthermore, we have attempted to demonstrate the synthetic utility of shikimic acid by covering the most important synthetic modifications and related applications, namely, synthesis of Tamiflu and derivatives, synthetic manipulations of the main functional groups, and its use as biorenewable material and in total synthesis. Given its rich chemistry and availability, shikimic acid is undoubtedly a promising platform molecule for further exploration. Therefore, in the end, we outline some challenges and promising future directions.

Decane-1,2-diol derivatives as potential antitumor agents for the treatment of glioblastoma.

Glioblastoma remains the most common and aggressive type of malignant brain tumor among adults thus, considerable attention has been given to discovery of novel anti-tumor drugs for its treatment. This study reports the synthesis of a series of twelve novel decane-1,2-diol derivatives and evaluation of its anti-tumor activity in mammalian glioblastoma cell lines, U87 and LN229. Starting from decane-1,2-diol, several derivatives were prepared using a diversity oriented synthesis approach through which a small library composed of esters, silyl ethers, sulfonates, sulfites, sulfates, ketals, and phosphonates was built. The decane-1,2-diol ditosylated derivative, DBT, found to have higher cytotoxicity than the standard drug cisplatin, has IC50 value of 52 µM in U87 and 270 µM in LN229. Migration analysis of U87 cell line treated with the DBT indicated its ability to effectively suppress proliferation during initial hours of treatment and decrease anti-proliferative property over time. Additionally, DBT was assessed for its role in apoptosis, oxidative stress and caspase 3/7 activation in U87. Interestingly, our experiments indicated that its cytotoxicity is independent of Reactive oxygen species induced caspase 3/7 activity. The compound also exhibited caspase independent apoptosis activity in U87. DBT treatment led to G1/S cell cycle arrest and apoptosis induction of glioma cell lines. In addition, we identified 1533 genes with significant changes at the transcriptional level, in response to DBT. A molecular docking study accounting for the interaction of DBT with NMDA receptor disclosed several hydrogen bonds and charged residue interactions with 17 amino acids, which might be the basis of the DBT cytotoxicity observed. We conclude that this molecule exerts its cytotoxicity via caspase 3/7 independent pathways in glioblastoma cells. Concisely, simple decane-1,2-diol derivatives might serve as scaffolds for the development of effective anti-glioblastoma agents.