Design, synthesis, and biological evaluation of tetrahydroquinolinones and tetrahydroquinolines with anticancer activity

Abstract

Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and the United States and the second leading cause of cancer related mortality. A therapeutic strategy used for the treatment of CRC involves targeting the intracellular levels of reactive oxygen species (ROS). In this study, we synthesized a series of novel tetrahydroquinolinones and assessed their ability to inhibit CRC growth and proliferation by evoking cellular stress through ROS. Our results revealed that (2-oxo-4-phenyl-5,6,7,8-tetrahydroquinolin-8-yl) N-(3-fluorophenyl)carbamate (20d) exhibited in vitro antiproliferative activity at micromolar concentrations. The compound also suppressed colony formation and the migration of HCT-116 cells, as well as deregulated the expression of several proteins involved in cell proliferation and metastasis. Furthermore, 20d induced massive oxidative stress by disrupting the balance of cells survival resulting in autophagy via the PI3K/AKT/mTOR signaling pathway. These findings suggest that this tetrahydroquinolinone can be an ideal lead compound for drug discovery based on quinone derivatives.

Synthetic return of the Meldrum’s acid. 2,2-dimethyl-1,3-dioxane- 4,6-dione assisted formation of tetrahydroquinolin-2-one derivatives. Short synthetic pathway to the biologically useful scaffold

“…Recently we focused our synthetic efforts on the preparation of 2-pyridone moiety fused with a saturated ring, as well as on the preparation of a permanently aromatic similar system isosteric with pyridone scaffold 10,11 . According to our anticipation and molecular docking results, the referred compounds have exhibited anticancer activity however the convenience of synthesis was far from perfect.…”

“…Previously used in our laboratory method for the synthesis of tetrahydroquinolin-2-one scaffold 10,11 was a compilation and adaptation of a procedure described by several research groups [22][23][24] . Due to the problem with direct procedure with the use of benzoylacetate ammonium acetate and cyclohexanone, where in situ formation of amide should take place followed by the subsequent reaction with cyclohexanone.…”

Synthesis of β-Carbonyl α-Iminoamides by Double Insertion of Isocyanides into Aldehydes

“…Both the carbonyl and imino groups are facile to be reduced with LiAlH 4 , leading to amino alcohol 10 in 94% yield . Interestingly, product 3a undergoes condensation and annulation with cyclohexanone to furnish the cyclic product 11 …”