The development of pyridazinone-based andrographolide derivatives as anti-cancer agents with the ability of inhibiting the TFAP4/Wnt/β-catenin signaling pathway

Emerging evidence indicated that natural andrographolide and its derived compounds could exert anti-cancer effects on a broad range of Cancer cells by several mechanisms of actions. However, the potent andrographolide derivatives with novel structures are needed and the comprehensive understanding of the underlying mechanisms of actions are still lacking. In this work, we reported the pyridazinone-based anti-cancer andrographolide derivative A61, which is superior to the widely-used anti-cancer drug 5-FU (around 5-fold more potent), it showed high potency to inhibit the growth and migration of a panel of Cancer cells, in which the gastric Cancer cells exhibited the highest drug sensitivity. Preliminary anti-cancer mechanistic studies indicated that A61 exerted its anti-gastric Cancer effect by inducing cell Apoptosis through intrinsic mitochondria-mediated pathways and arresting cell circle at S phase. Further exploration at the molecular level indicated that compound A61 may inhibit the transcriptional activity and nuclear localization of TFAP4 in gastric Cancer cells by inhibiting the TFAP4/Wnt/β-catenin signaling pathway. For the first time, the TFAP4/Wnt/β-catenin signaling pathway was found to be responsible for the anti-cancer activity of andrographolide derivative. In addition, A61 was demonstrated to have significantly increased bioavailability in rats compared with andrographolide. This work provides pertinent information for the understanding of the anti-cancer mechanism by this class of compounds.

Andrographolide; Anti-cancer; Design and synthesis; Mechanistic studies; TFAP4; Wnt/β-catenin signaling pathway.