Mass spectrometry-based metabolomics approach and in vitro assays revealed promising role of 2,3-dihydroquinazolin-4(1H)-one derivatives against colorectal cancer cell lines.

Colorectal cancer (CRC) is the most frequent form of gastrointestinal cancer and one of the major causes of human mortality worldwide. Many of the current CRC therapies have limitations due to multidrug resistance and/or severe side effects. Quinazoline derivatives are promising lead compounds with a wide range of pharmacological actions. In this study, the effect of seven synthesized 2,3-dihydroquinazolin-4(1H)-one analogues as potential anticancer agents against two CRC cell lines (HCT116 and SW480) was investigated using cell viability proliferation, migration, adhesion and invasion assays. A liquid chromatography-mass spectrometry (LC-MS/MS) metabolomics approach was used to identify the underlying biochemical pathways disturbed in treated-HCT116 cells. Cell viability proliferation assay revealed that four compounds (C2, C3, C5, and C7) had IC50 < 10 µM with C5 displaying the most potent cytotoxic effect (IC50 1.4 and 0.3 µM against HCT116 and SW480, respectively). Additionally, the compounds showed suppression of wound closure after 72 h, and both C2 and C5 significantly decreased the number of adherent cells and suppressed HCT116 cells invasion. Metabolomics study revealed that C5 induced significant perturbations in the level of several metabolites including spermine, polyamines, glutamine, creatine and carnitine, and altered biochemical processes essential for cell proliferation and progression such as amino acids biosynthesis and metabolism, redox homeostasis, energy related processes (e.g., fatty acid oxidation, second Warburg like effect) and one-carbon metabolism. Our findings indicate that 2,3-dihydroquinazolin-4(1H)-one analogues, particularly C5, have promising anticancer properties, and shed light on the role of metabolomics in identifying new therapeutic targets and providing better understanding of the pathways altered in treated cancer cells.

Molecular and metabolic alterations of 2,3-dihydroquinazolin-4(1H)-one derivatives in prostate cancer cell lines.

Prostate cancer (PC) is the second most common tumor in males worldwide. The lack of effective medication and the development of multidrug resistance towards current chemotherapeutic agents urge the need to discover novel compounds and therapeutic targets for PC. Herein, seven synthesized 2,3-dihydroquinazolin-4(1H)-one analogues were evaluated for their anticancer activity against PC3 and DU145 cancer cell lines using MTT, scratch-wound healing, adhesion and invasion assays. Besides, a liquid chromatography mass spectrometry (LC-MS)-based metabolomics approach was followed to identify the biochemical pathways altered in DU145 cancer cells upon exposure to dihydroquinazolin derivatives. The seven compounds showed sufficient cytotoxicity and significantly suppressed DU145 and PC3 migration after 48 and 72 h. C2 and C5 had the most potent effect with IC50 < 15 µM and significantly inhibited PC cell adhesion and invasion. Metabolomics revealed that C5 disturbed the level of metabolites involved in essential processes for cancer cell proliferation, progression and growth including energy production, redox homeostasis, amino acids and polyamine metabolisms and choline phospholipid metabolism. The data presented herein highlighted the importance of these compounds as potential anticancer agents particularly C5, and pointed to the promising role of metabolomics as a new analytical approach to investigate the antiproliferative activity of synthesized compounds and identify new therapeutic targets.

Plasma drop and thin-film revealed distinguished molecular structure in pre-eclampsia: An investigation using synchrotron Fourier-transform infrared microspectroscopy.

Pre-eclampsia (PE) is a serious pregnancy-related disorder and the leading cause of maternal and fetal mortality and morbidity worldwide. The etiology of PE is poorly understood and a definitive diagnosis is still lacking. Herein, we used synchrotron-FTIR microspectroscopy as a new analytical tool to investigate the molecular changes in the structure and intensity of lipids (spectral range 3050-2800 cm-1) and protein-carbonyl (spectral range 1855-1485 cm-1) components of the plasma and link them to the pathogenesis of the disease. In the lipid region, an increase in the CH2 and CH3 peaks intensity was noticed in PE group compared to normotensive pregnancy reflecting abnormalities in the lipid profile and a high level of LDL. Increased CH2/CH3 ratio and red shifts were observed in the lipid region in PE highlighting structural variations of lipids and transformation of conformation of lipid tails. In the protein-carbonyl region, a decrease in the amide I and II absorption signals in the plasma of PE compared to normotensive controls was evident, and a red shift was noticed in the amide I region reflecting conformational changes and rearrangement in the α-helix secondary structure of the protein. Moreover, malondialdehyde level and lipid carbonyl peak at 1743 cm-1 were higher and more intense in PE due to the oxidative stress condition in PE. Spectral analysis of plasma drop from PE revealed that lipid and protein components tend to concentrate more in the central region of the drop, and that the most intense wavenumber values for the lipid and amide I region in the plasma drop were very comparable to their analogous in plasma film. Taken together, the current work provides evidence of the promising role of synchrotron-FTIR microspectroscopy in providing a better understanding of the pathophysiology of PE.