Green one-pot synthesis of a novel furan-2(3H)-one derivative: in vitro antiproliferative activity and DFT study

Abstract

This research details the green synthesis of a series of novel, biologically active heterocyclic compounds. These compounds were efficiently prepared by reacting (3Z)-3-((benzo[1,3]dioxol-6-yl)methylene)-5-phenylfuran-2(3H)-one (L) with various electrophilic and nucleophilic reagents under microwave irradiation. The newly synthesized compounds were subsequently subjected to comprehensive in vitro cytotoxicity assessments against a panel of human cancer cell lines, including hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT116), and breast adenocarcinoma (MCF-7), alongside a normal human fibroblast cell line (BJ-1) to evaluate selectivity. The cytotoxic screening against HCT116 yielded compelling results; compound L13 demonstrated superior cytotoxicity, as well as compounds L3, L4, L5, and LN exhibiting comparable robust activity, while the remaining synthesized products showed mild cytotoxicity. For the MCF-7 cell line, compounds L3, L4, and L13 displayed superior cytotoxic activities, complemented by similar strong effects from L2, LN, and L5. The remaining substances showed moderate cytotoxicity. In the context of the HepG-2 cell line, compounds L1, L2, L3, L4, and L13 all exhibited superior cytotoxic actions, with the rest of the compounds presenting comparable efficacy. To ascertain therapeutic potential, the compounds were also tested on the BJ-1 normal fibroblast cell line. Here, compounds L1, L8–10, and L13 presented notable cytotoxic activities, while L2, L3, L4, L6, and L12 showed comparable cytotoxicity. Crucially, a contrasting analysis of cytotoxicity data between the cancerous and normal cell lines allowed us to identify highly promising candidates. Compounds L2–L5, L13, and LN are highlighted as excellent candidates for treating both liver and breast cancer tumors, indicating a broad spectrum of activity. Furthermore, compounds L1, L6–L8, L10, L11, and L12 are presented as exclusively effective and specifically designed anticancer candidates for treating human liver cancer tumors, suggesting a more targeted therapeutic profile. To elucidate the underlying molecular mechanisms, a density functional theory (DFT) study was performed on the new compounds. This theoretical investigation revealed that derivatives L3, L4, LN, and L5 possess the maximum electron transfer capability, a key property hypothesized to be crucial for inhibiting cancer cell proliferation. DFT analysis provides valuable theoretical support for the observed potent biological activities and guides future rational drug design.