Synthesis and biological evaluation of piperlongumine analogues containing indoline or tetrahydroquinoline as anticancer agents through apoptosis induction

Abstract

The investigation of natural products and their derivatives or analogues represents a critical avenue for the discovery of novel drug candidates. Piperlongumine (PL), a natural alkaloid, was originally isolated from the roots of Piper longum L., and has been reported to possess various biological activities. In this study, we designed and synthesized a total of 24 PL analogues by retaining the trimethoxystyryl group, whereas the piperidinone part of PL was replaced by indoline or 1,2,3,4-tetrahydroquinoline. The synthesized analogues were characterized by ¹H NMR, ¹³C NMR, and HRMS analysis. The in vitro anticancer activity of the compounds against lung cancer cells A549, breast cancer cells MDA-MB-231 and liver cancer cells HepG2 were detected by MTT method. Notably, compound 13d exhibited an IC₅₀ value of 8.97 ± 0.22 µM against HepG2 cells and showed selectivity towards human normal hepatocyte (LX-2, IC₅₀ = 49.88 ± 3.39 µM). In addition, morphological changes, cell growth curve and colony formation indicated that compound 13d could significantly inhibit proliferation of HepG2 cells. Furthermore, Hoechst 33342 staining and flow cytometry confirmed that compound 13d induced apoptosis in HepG2 cells, and activation of apoptosis markers caspase 3 and PARP was further observed via western blot analysis. Our study indicates that compound 13d may be a potent lead candidate for cancer therapy against liver cancer.