Efficient gram-scale synthesis and preclinical evaluation of an escin-derived therapeutic for ovarian cancer.

Ovarian cancer is the most lethal gynecologic malignancy, characterized by a poor five-year survival rate for patients with advanced-stage disease. EV-S008, an escin derivative, exhibits potent anti-ovarian cancer activity; however, its preclinical development has been hindered by inefficient synthetic methodologies. In this study, we report a rational, seven-step synthetic route for EV-S008 that achieves a 40-fold increase in yield and produces material with 99.3% purity on a gram scale. EV-S008 demonstrated broad cytotoxicity across multiple human ovarian cancer cell lines, with IC50 values ranging from 1.2 to 11 μM. Pharmacokinetic analyses revealed that intraperitoneal (IP) administration achieved favorable bioavailability and sustained plasma drug level (prolonged T1/2) compared to oral dosing, and produced remarkably high concentrations in both ovary (28,810 ng/g) and peritoneal fluid (922,500 ng/mL), both notably exceeding in vitro IC50 values. In an ES-2-Luc xenograft nude mouse model, dose-dependent efficacy was observed, with IP administration of 10 mg/kg EV-S008 achieving 78% tumor growth inhibition (TGI) and significantly prolonged survival (p = 0.005). Altogether, these findings establish EV-S008 as a promising therapeutic candidate for ovarian cancer treatment via intraperitoneal delivery.