Identification of 3,5-Bis (2-Ethoxybenzylidene) Piperidin-4-one as a Monocarbonyl Curcumin Analog Inhibiting Cell-Intrinsic NF-κB Activity in 4T1 Breast Cancer Cells

Abstract

Although numerous biological properties of curcumin, a bioactive polyphenol from the rhizome of turmeric (Curcuma longa), have been documented, its poor bioavailability limits clinical application. Therefore, identifying new analogs with improved pharmacokinetics and pharmacological properties is essential. Given that curcumin and its related compounds are known to inhibit cancer cell progression and metastasis through nuclear factor-kappaB (NF-κB) signaling inhibition, we investigated 58 newly synthesized, structurally diverse monocarbonyl curcumin analogs. Their inhibitory effects on intrinsic NF-κB activity were assessed in breast cancer cells using the 4T1 cell line expressing a luciferase NF-κB reporter. Among the 58 monocarbonyl curcumin analogs, 3,5-bis(2-ethoxybenzylidene)piperidin-4-one (E145) exhibited potent inhibition of NF-κB activity in 4T1 breast cancer cells. Based on the structure–activity relationship analysis, the central heterocyclic monocarbonyl linker structure of E145 contributed to its increased potency in NF-κB inhibition.