BBB penetration-targeting physicochemical lead selection: Ecdysteroids as chemo-sensitizers against CNS tumors

The anticancer potential of ecdysteroids, especially their chemo-sensitizing activity has recently gained a substantial scientific interest. A comprehensive physicochemical profiling was performed for a set of natural or semi-synthetic ecdysteroids (N=37) to identify a lead compound against central nervous system (CNS) tumors. Calculated properties, such as lipophilicity (clogP), topological polar surface area (TPSA), brain-to-plasma ratio (clogBB) along with the measured blood-brain barrier specific in vitro permeability (logP_e) were evaluated in parallel. Compounds with the highest CNS-availability predicted (clogBB>0.0 and logP_e>-6.0) showed moderate to high lipophilicity (clogP=3.89-5.25), relatively low TPSA (94.45Ų), and shared a common apolar 2,3- and 20,22-diacetonide motif (25, 30-33). These ecdysteroids were selected for testing their capacity to sensitize SH-SY5Y neuroblastoma cells to vincristine. All of the five tested compounds exerted a remarkably strong, dose dependent chemo-sensitizing activity: at 2.5-10.0μM ecdysteroids increased the cytotoxic activity of vincristine one to three orders of magnitude in (e.g., from IC₅₀=39.5±2.9nM to as low as 0.056±0.03nM). Moreover, analysis of the combination index (CI) revealed outstanding synergism between ecdysteroids and vincristine (CI₅₀=0.072-0.444). Thus, based on drug-likeness, physchem character and in vitro CNS activity, compound 25 was proposed as a lead for further in vivo studies.