Gemma Triola

cis- versus trans-Ceramides: Effects of the Double Bond on Conformation and H-Bonding Interactions

Natural ceramides (Cers) possess a trans double bond between C4 and C5 of the sphingoid chain. This double bond is critical to their cell signaling properties. Both a change from trans to cis and the saturation of this site lead to changes in or loss of biological activity. To explore the conformational impact of the cis double bond, through-bond, and through-space interactions were investigated in hydrated Cers by multidimensional (1)H and (13)C NMR spectroscopy. Unlike trans-Cer, the cis-isomer exhibited not one but two broad yet resolved resonances for the protons in C1-OH and C3-OH, much like dihydroceramide (DHCer). Temperature-dependent studies and partial isotopic labeling of cis-Cer revealed that relative to trans-Cer, these two OH groups form weaker hydrogen bonds, particularly in the case of C1-OH. Our results also suggest that the cis double bond twists, slightly, the orientation of HO-C1 with respect to HO-C3, thus weakening the hydrogen-bonding network formed between the two OH groups of cis-Cer and bound water molecules. The alteration of the local network of H-bonds may account for the differences observed in the biological activity of the two isomers.

Squaramides with cytotoxic activity against human gastric carcinoma cells HGC-27: synthesis and mechanism of action

A series of squaramates and squaramides have been synthesized and their cytotoxic activity has been investigated in different cancer cell lines. Among the studied compounds, squaramide 34 showed a potent and selective cytotoxicity against the human gastric cancer cell line HGC-27. Studies directed to elucidate the mechanism of induced cell death were performed. Cell cycle distribution analysis and cell death studies showed that compound 34 induces cell cycle arrest at the G1 phase and caspase-dependent apoptosis. In conclusion, squaramide 34 can be considered a potential anticancer agent for gastric carcinoma.

Synthesis of Squaramides with Anti-tumor Activity

In this study, the cytotoxic effects of different squaramides were tested against diverse cancer cells, such as HGC-27, HeLa, T98 and U87 cells, and non-cancer cells, such as EK293, MDCK and Vero cells. The best results were observed in a disubstituted squaramide that showed an IC50 of 1.81 μM against HGC-27 cells, which is a considerably lower value than the IC50 values observed in the rest of the cell lines. Therefore, this squaramide and its derivatives could be promising molecules for the treatment of gastric carcinoma. nFurthermore, the mechanism of action of this compound was evaluated. The outcomes indicated that the decrease in cell viability produced by the squaramide is probably caused by G0/G1 cell cycle arrest and caspase-mediated apoptosis. Additionally, the cell death produced by this compound was accompanied by autophagy induction and no signs of cathepsin-mediated cell death and necroptosis were observed.