“Efficient Gram-Scale Synthesis and Preclinical Evaluation of an Escin-Derived Therapeutic for Ovarian Cancer” 已在 Bioorganic & Medicinal Chemistry 期刊上發表

Abstract

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 T_1/2) 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.

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