Synthesis and structure-activity relationships of novel ecdysteroid dioxolanes as MDR modulators in cancer

Abstract

Ecdysteroids, molting hormones of insects, can exert several mild, non-hormonal bioactivities in mammals, including humans. In a previous study, we have found a significant effect of certain derivatives on the ABCB1 transporter mediated multi-drug resistance of a transfected murine leukemia cell line. In this paper, we present a structure-activity relationship study focused on the apolar dioxolane derivatives of 20-hydroxyecdysone. Semi-synthesis and bioactivity of a total of 32 ecdysteroids, including 20 new compounds, is presented, supplemented with their complete 1H- and 13C-NMR signal assignment.

Figure 1

Semi-synthetic transformations of 20E and structures of the products obtained. Substituents of the reagent oxo-compound (X¹/X² and X³/X⁴) typically correspond to R¹/R² and R²/R³, respectively, except for compounds 18 and 19, where the reagent was methyl-ethyl ketone. 15 was obtained as a side product from the synthesis of 23.

Figure 2

Stereostructure of 22. Red arrows indicate the detected ROESY steric proximities, the blue numbers give the characteristic ¹H, and the black numbers the ¹³C chemical shifts.

Figure 3

Fraction affected (Fa) vs. combination index (CI) value plot for compounds 5 and 15, in comparison with the original lead compound 1. Error bars represent 95% confidence intervals by means of serial deletion analysis performed with the CompuSyn software. The 2,3-mono-dioxolane derivative 15 represents significantly stronger synergism with doxorubicin than the corresponding 20,22-dioxolane derivative 5 at practically all activity levels, and above Fa = 0.7 (which, in case of cancer, matters the most [10]) it is also stronger than compound 1.

Figure 4

SAR summary for compounds 1–33. “Greater than” symbols denote stronger synergistic activities, i.e., lower weighted average CI values when applied together with doxorubicin.