Design, synthesis and anticancer activity studies of 3-(coumarin-3-yl)-acrolein derivatives: Evidenced by integrating network pharmacology and vitro assay

Abstract

Coumarin derivatives have diverse structures and show various significant biological activities. Aiming to develop more potent coumarin derivatives for cancer treatment, a series of coumarin acrolein hybrids were designed and synthesized by using molecular hybridization approach, and investigated for their antiproliferative activity against A549, KB, Hela and MCF-7 cancer cells as well as HUVEC and LO2 human normal cells. The results indicated that most of the synthesized compounds displayed remarkable inhibitory activity towards cancer cells but low cytotoxicity on normal cells. Among all the compounds, 5d and 6e were the most promising compounds against different cancer cell lines, especially for A549 and KB cells. The preliminary action mechanism studies suggested that compound 6e, the representative compound, was capable of dose-dependently suppressing migration, invasion and inducing significant apoptosis. Furthermore, the combined results of network pharmacology and validation experiments revealed that compound 6e induced mitochondria dependent apoptosis via the PI3K/AKT-mediated Bcl-2 signaling pathway. In summary, our study indicated compound 6e could inhibit cell proliferation, migration, invasion and promote cell apoptosis through inhibition of PI3K/AKT signaling pathway in human oral epidermoid carcinoma cells. These findings demonstrated the potential of 3-(coumarin-3-yl)-acrolein derivatives as novel anticancer chemotherapeutic candidates, providing ideas for further development of drugs for clinical use.

Synthesis of novel coumarin-triazole hybrids and first evaluation of the 4-phenyl substituted hybrid loaded PLGA nanoparticles delivery system to the anticancer activity

“…For this reason, despite the cumulative release in the second 24 h (figure 8(b)), cell viability may increase compared to the first 24 h. On the other hand, considering the hydrophobic character of the PLGA nanoparticles compared to the free molecule 21, the delivery time and dose of the activated substance into the cell may differ and the duration of the cytotoxic effect may increase due to the increase in the exposure time to the active substance. In fact, as emphasized in the literature regarding coumarin derivatives, molecule 21 can suppress the growth and proliferation of cancer cells even at low doses and may not have a significant toxic effect on normal cells [64,65]. This may be further evidence that coumarins are a promising class of anti-tumor drugs with high selectivity.…”