Design, Synthesis, and Anticancer Activity Studies of Novel Quinoline-Chalcone Derivatives

Abstract

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC50 values of 1.38, 5.34, and 5.21 µM, respectively. The structure–activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.

Chalcones and Gastrointestinal Cancers: Experimental Evidence

“…Similar to their activity in colon cancer cells, chalcones also mostly stop cell cycle progression at the G2/M phase in gastric cancer cells. Guan et al [ 49 ] documented a strong antiproliferative effect of the newly synthesized quinoline chalcone derivative 12e against the MGC-803 gastric cancer cell line. Among other effects, this chalcone-induced G2/M arrest was followed by the activation of caspases-3 and -9, indicating the mitochondrial pathway of apoptosis.…”

“…In the light of these facts, several natural and synthesized chalcones possess pro-oxidant activity, which is connected to their pro-apoptotic and cytotoxic potential in the treatment of gastric cancer. ROS production has been observed in human gastric cell line SGC-7901 after treatment with the ISL analog ISL-17 [ 52 ] and in MGC-803 and SGC-7901 cells following treatment with the novel quinoline–chalcone derivative 12e [ 49 ]. Fu et al presented indirect evidence that ROS production was possibly associated with cytotoxicity in MGC-803 cells after (E)-3-(3,5-difluorophenyl)-1-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one (chalcone 5) treatment [ 182 ].…”

Synthesis and SAR investigation of biphenylaminoquinoline derivatives with benzyloxy substituents as promising anticancer agents

“…Previous investigations have underscored the pivotal role of biphenyl derivatives in the realm of cancer drug discovery. Moreover, substantial empirical evidence supports the notion that the integration of the phenyl core with the esteemed quinoline moiety confers potent antitumor properties (Abdellatif et al, 2017;Guan et al, 2021;Joshi et al, 2017;Wu et al, 2023;Zdrazil & Guha, 2018). Drawing inspiration from these pertinent observations, we present our synthetic design strategy, as illustrated in Figure 2.…”

Application of Quinoline Ring in Structural Modification of Natural Products

“…Guan and colleagues [ 104 ] synthesized chalcone quinoline derivatives 145 – 146 ( Figure 25 ) ( Table 10 ) and evaluated the in vitro antiproliferative activity of the compounds against MGC-803, HCT-116, and MCF-7. The chemotherapy medication 5-Fluorouracil (5-Fu) was used as a positive control.…”