Design, synthesis, and biological evaluation of C-28 carboxyl derivatives of Hederacoside C as anti-inflammatory agents for acute lung injury

Hederacoside C, a bioactive triterpenoid saponin isolated from the dried roots of the Ranunculaceae plant Pulsatilla chinensis, has demonstrated therapeutic efficacy in murine models of nephritis, acute lung injury, and inflammatory bowel disease. However, its further development as a drug candidate has been hampered by hemolytic toxicity and poor oral bioavailability. Based on published evidence that the free carboxyl group at the C-28 position is closely associated with hemolytic activity, a series of C-28 carboxyl derivatives was rationally designed and synthesized with the aim of attenuating hemolytic liability while preserving or enhancing anti-inflammatory potency. Following in vitro anti-inflammatory evaluation and cytotoxicity assessment, compound HSC-4 was identified as the most promising candidate for further in vivo pharmacological studies. Notably, HSC-4 exhibited significant anti-inflammatory efficacy in both a murine systemic sepsis model and an acute lung injury model. An acute toxicity study further demonstrated that HSC-4 did not cause significant hepatotoxicity or nephrotoxicity in KM mice at doses up to 400 mg/kg over five consecutive days. These findings suggest that HSC-4 represents a promising lead compound for the development of novel anti-inflammatory therapeutics, pending further hemolytic activity assessment and pharmacokinetic characterization.