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

Abstract

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.

Figure 1

Examples of modified quinolinone cores that induced apoptosis in various cancer cells.

Figure 2

Synthetic pathways for the preparation of new tetrahydroquinolinone derivatives: (a) RCH₂X, K₂CO₃/DMF, 60 °C, 5 h; (b) 24% NH₃ aq, 50 °C, 24–72 h; (c) TsOH/toluene, reflux, 12 h; (d) PhP(O)Cl₂, 160 °C, 16 h; (e) Ag₂CO₃, CH₃I/CHCl₃, RT, 12 h.

Figure 3

Effect of 4a on colony formation and cell viability. (a) Representative photos of the colony formation assay after the treatment of A549 cells with increasing concentrations of 4a. (b) Quantification of the colony formation assay. (c) Effect of 4a on cell viability after incubation with compound for 72 h. Data represent the mean ± SEM of n = 3 independent experiments. *p < 0.01, **p < 0.001, ***p < 0.0001, and ****p < 0.00001.

Figure 4

Analysis of cell cycle distribution after treatment of A549 cells with 4a. Data represent the mean ± SEM of n = 3 independent experiments. *p < 0.01, **p < 0.001, ***p < 0.0001, and ****p < 0.00001.

Figure 5

Detection of apoptosis by flow cytometry. (a) Representative dot plots after treatment of A549 cells with 4a. (b) Quantitation of A549 cells after Annexin V-FITC/7-AAD staining. (c) Detection of caspase-3/7 activation in 4a-treated A549 cells, presented as representative histograms. (d) Quantification of analysis from (c). Data represent the mean ± SEM of n = 3 independent experiments. *p < 0.01, **p < 0.001, ***p < 0.0001, and ****p < 0.00001.

Figure 6

Western blotting analysis showing the effects of 4a on the expression of apoptosis-related proteins in the A549 cell line. Full-length Western blots are presented in the supplementary information.

Figure 7

Conclusion of structure–activity relationship studies of the presented tetrahydroquinolinone derivatives.