Meldrum's acid assisted formation of tetrahydroquinolin-2-one derivatives a short synthetic pathway to the biologically useful scaffold.

A new method for the preparation of tetrahydroquinolin-2-one derivatives is presented. This approach involves a two-step reaction between enaminones and acylating agents, immediately followed by electrophilic cyclization, all within a single synthesis procedure, eliminating the need to isolate intermediates. The entire process is facilitated by the use of acyl Meldrum's acids which not only shortens the preparation time of the substrates but also easily extends the range of substituents That can be used. The method's scope and limitations were evaluated with various reagent combinations thus demonstrating its general applicability to the synthesis of tetrahydroquinolin-2-one core. Interestingly, some exceptions to the regular reaction pathway were observed when a strong EDG (electron donating group) was introduced via acyl Meldrum's acids. The underlying mechanism of this phenomenon was elucidated during the investigation.

Tetrahydroquinolinone derivatives exert antiproliferative effect on lung cancer cells through apoptosis induction.

The anticancer properties of quinolones is a topic of interest among researchers in the scientific world. Because these compounds do not cause side effects, unlike the commonly used cytostatics, they are considered a promising source of new anticancer drugs. In this work, we designed a brief synthetic pathway and obtained a series of novel 8-phenyltetrahydroquinolinone derivatives functionalized with benzyl-type moieties at position 3. The compounds were synthesized via classical reactions such as nucleophilic substitution, solvent lysis, and condensation. Biological evaluation revealed that 3-(1-naphthylmethyl)-4-phenyl-5,6,7,8-tetrahydro-1H-quinolin-2-one (4a) exhibited potent cytotoxicity toward colon (HTC-116) and lung (A549) cancer cell lines. Analysis of the mechanism of action of compounds showed that compound 4a induced cell cycle arrest at the G2/M phase, leading to apoptotic cell death via intrinsic and extrinsic pathways. Taken together, the findings of the study suggest that tetrahydroquinolinone derivatives bearing a carbonyl group at position 2 could be potential lead compounds to develop anticancer agents for the treatment of lung cancers.

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

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.

From tryptophan to novel mitochondria-disruptive agent, synthesis and biological evaluation of 1,2,3,6-tetrasubstituted carbazoles.

Mitochondrial targeting plays an important role in anticancer therapy. The Mn(III)-promoted cyclization of 5-(1H-indol-3-yl)-3-oxopentanoic acid allow to obtain novel substituted carbazole derivatives that can act as mitochondria-disruptive agents. The starting materials used for the synthesis of these new aminocarbazoles are oxopentanoate derivatives of tryptophan. The scope and limitation of this method of synthesis are determined by a series of experiments. The prepared carbazole derivatives are screened for their in vitro anticancer activity against a broad panel of human cancer cells and normal cell lines. Among the tested compounds, the most active ones are examined further against human colon cancer cells (HCT-116) and human bone osteosarcoma (U-2 OS), in complex in vitro cellular assays, including studies on cell cycle distribution, intracellular compartmentalization, antimigratory properties, mitochondrial generation of reactive oxygen species, DNA damage, and type of cellular death. The results reveal that the synthesized compounds display potent oxidative activity inducing massive accumulation of DNA double-strand breaks, which lead to a parallel change in the assembly of mitochondria causing their dysfunction. These findings provide new leads for the treatment of colon cancer and osteosarcoma.