Design, synthesis, and biological evaluation of shikonin and alkannin derivatives as potential anticancer agents via a prodrug approach

Abstract

To minimize the cytotoxicity of shikonin and alkannin that arises through the generation of reactive oxygen species (ROS) and alkylation of the naphthazarin ring, two series of novel core-scaffold-modified shikonin and alkannin derivatives were designed. These derivatives, which differ in their configurational and positional isomerism (R-, S-, and 2- and 6-isomers) were synthesized in high enantiomeric excess (>99 % ee). The selectivity of the dimethylated derivatives was significantly higher than the parent shikonin in vitro, but some side effects were still observed in vivo. Surprisingly, the dimethylated diacetyl derivatives with poor anticancer activity in vitro showed tumor-inhibiting effects similar to paclitaxel without any toxicity in vivo. The anticancer activity of these derivatives is in agreement with their low ROS generation and alkylating capacity, emphasizing their potential as prodrugs. This strategy provides means to address the nonspecific cytotoxicity of naphthazarin analogues toward normal cells.

Keywords: alkannin; alkylation; antitumor agents; oxidation; prodrugs; shikonin.