This study examines the pharmacokinetics and bioavailability of phlorotannins from Ecklonia cava in rats following intravenous and oral administration. Known for their potent antioxidant, anti-inflammatory and many other bioactivities, these phlorotannins, particularly dieckol, 8,8′-bieckol, and phlorofucofuroeckol-A (PFF-A), were analyzed using high-performance liquid chromatography coupled with tandem mass spectrometry. Intravenous administration at 10 mg/kg allowed detectability in plasma for up to 36 h for dieckol and 8,8′-bieckol, but only 2 h for PFF-A. Oral administration at doses of 100 mg/kg and 1000 mg/kg showed limited detectability, indicating low bioavailability and rapid clearance, particularly for PFF-A. The pharmacokinetic data suggest non-linear increases in the maximum plasma concentration (C_max) and area under the curve (AUC) with increasing doses, pointing to significant challenges in achieving systemic availability of these eckols through oral administration. This study underscores the necessity for advanced formulation strategies and alternative routes of administration to enhance systemic bioavailability. At the same time, this result also suggests their effects may be through non-systemic pathways such as gut microbiome modulation or lipid-rich tissue targeting. The findings lay a crucial foundation for the further development of Ecklonia cava phlorotannins as therapeutic agents, offering insights into their pharmacokinetic behavior and informing enhancements in future clinical utility.

Dieckol, a phlorotannin from Ecklonia cava, has shown potential for use as an anticancer agent that selectively kills cancer cells. However, it is necessary to amplify its potency without damaging its inherent safety in order to develop it as a competitive chemotherapeutic. Here, we explored the controlled O-acylations of dieckol. Acyl groups could be consistently introduced to the 6-O position of dieckol with a high regioselectivity, which was confirmed by NOESY, HMBC and HSQC spectroscopies. In cytotoxicity studies on the newly synthesized 6-O-acetyl, 6-O-benzoyl dieckols and previously synthesized 6-O-alkyl dieckols against A549 vs. normal cells, all of the derivatives showed low cytotoxicity in normal cells with an IC₅₀ of 481–719 μM, and highly structure-dependent cytotoxicity in A549 cells with an IC₅₀ of 7.02 (acetyl)−842.26 (benzyl) μM. The selectivity index also showed a large structure dependency in the range of 0.67 (benzyl)–68.58 (acetyl). An analysis of the structure–activity relationship indicated that the activity was dramatically reduced in the presence of a benzene ring and was highly increased in the presence of small polar substituents. Conclusions: Controlled mono-O-modifications of dieckol could be a powerful tool to enhance the anticancer activity of dieckol, thus contributing to the development strategy for dieckol-based chemotherapeutics.

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