Design, Synthesis, and Anti-Hepatocellular Carcinoma Evaluation Revealed by Transcriptome Analysis of Epimeric Sesquiterpene Lactones: Trilobolide-6-O-isobutyrate Analogues.

Abstract

Hepatocellular carcinoma is a malignant neoplasm that ranks sixth in global incidence and fourth in global mortality. In this study, based on the splicing principle and prodrug synthesis strategies, a total of 18 new sesquiterpene lactone derivatives, consisting of seven mustard derivatives and 11 amine adducts, were designed and synthesized using the sesquiterpene lactone epimers 1 and 2 as parent molecules. Their structures were characterized by means of NMR, HRESIMS, and X-ray crystallography data. Through the CCK8 assay, compound 11 exhibited the most potent inhibitory activity against HepG2 (IC₅₀ = 4.2 μM) and Huh7 (IC₅₀ = 4.9 μM) cells. Subsequent pharmacological experiments demonstrated that compound 18 could decrease the viability of two HCC cell lines in a time- and dose-dependent manner. Both compounds 11 and 18 were capable of inducing cell apoptosis, arresting the cell cycle progression, and inhibiting cell proliferation and migration in HepG2 and Huh7 cells. Further transcriptome analysis indicated that 18 possessed potential antitumor effects. Both 11 and 18 had favorable predicted ADME and physicochemical properties. Collectively, the findings of this study suggest that derivatives 11 and 18 are promising candidates for the treatment of hepatocellular carcinoma.