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.