Microbial and chemical transformations of euphorbia factor L1 and the P-glycoprotein inhibitory activity in zebrafishes

Euphorbia factor L1 (EFL1, 1) is a natural tri-ester of 6,17-epoxylathyrol with cancer multidrug resistance (MDR) reversal activity. Several EFL1 derivatives (2–9) were prepared by chemical and microbial transformations and their ability to inhibit P-glycoprotein (P-gp) activity was estimated. Six de-acylated derivatives (2–7) were obtained through base-hydrolysis of 1, and the base-catalysed hydrolysis via KOH and NaOH yielded different hydrolysed products of 1. Two biotransformed products (8–9) were directly obtained via microbial transformation of 1, and 8 was also formed by microbial conversion of the hydrolysed product 3. The P-gp modulation of 1–9 was assessed by a zebrafish model. The substrate 1 and its biotransformed product 9 as the tri-esters of lathyranes possessed the highest P-gp inhibitory activity with IC50 values of 34.97 and 15.50 µM, respectively, through down-regulating P-gp expression at the protein level rather than at MDR1 mRNA level.