Background: Pancreatic cancer is one of the most aggressive malignancies with limited therapeutic options, primarily due to late detection, invasive behavior, and resistance to chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling axis is constitutively activated in pancreatic tumors, driving proliferation, survival, and metastasis. Natural product scaffolds such as piperic acid (PA) and 4-ethylpiperic acid (EPA) have shown anticancer activity, and incorporation of β-amino acids has been proposed to enhance stability and potency.
Methods: In this study, PA and EPA were conjugated with β-amino acids via carbodiimide-mediated coupling. The resulting conjugates were structurally confirmed using FTIR, NMR, and mass spectrometry. Biological evaluation was performed against PC-3 (prostate), PANC-1 (pancreatic), and HCT-116 (colorectal) cell lines using cytotoxicity (MTT assay), clonogenic, wound-healing, Matrigel invasion, 3D collagen invasion, cell scattering, and fluorescent gelatin degradation assays. Apoptosis was assessed by DAPI staining, caspase-3/7 activity, and PARP cleavage. Western blotting was used to evaluate PI3K/Akt/NF-κB, MAPK/ERK, MMP-2/9, TIMP-1, and E-cadherin expression, while cell cycle effects were analyzed using FUCCI sensor technology.
Results: Among all derivatives, conjugates 5 (PA-based) and 20 (EPA-based) exhibited the most potent activity. Conjugate 5 induced apoptosis in PANC-1 cells (IC₅₀ ~7.0 μM) via PARP and caspase-3 cleavage, BAX upregulation, BCL2/XIAP downregulation, G2 arrest, and inhibition of MAPK/ERK phosphorylation. Conjugate 20 strongly inhibited migration, clonogenicity, and invasion (IC₅₀ ~4.0 μM in PANC-1), suppressed invadopodia-mediated ECM degradation, downregulated MMP-2/9, induced TIMP-1, restored E-cadherin, and inhibited PI3K/Akt/NF-κB and mTOR/S6K signaling cascades.
Conclusion: PA and EPA β-amino acid conjugates display distinct but complementary anticancer mechanisms, with conjugate 5 acting as an apoptosis inducer and conjugate 20 as an anti-metastatic agent. Their ability to modulate PI3K/Akt/NF-κB signaling underscores their potential as promising leads for targeted pancreatic cancer therapy.
Keywords: Piperic acid conjugates; β-amino acids; Pancreatic cancer; PI3K/Akt/NF-κB signaling; Anticancer and anti-metastatic agents
How to cite this article: Shrivastava P, Upadhyay P, Swapna M, Madhavilatha B, Khatoon Y, Peela M, Sharma S, Sonu, Synthesis and Biological Evaluation of Piperic Acid and 4-Ethylpiperic Acid β-Amino Acid Conjugates as Anticancer Agents Targeting PI3K/Akt/NF-κB Signaling in Pancreatic Cancer Cells. Int J Drug Deliv Technol. 2026;16(4s): 821-830; DOI: 10.25258/ijddt.16.4s.95
Source of support: Nil
Conflict of interest: None