Design,Synthesis, and Biological Evaluation of Shikonin and Alkannin Derivatives as Potential Anticancer Agents via a Prodrug Approach |
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Authors: | Dr. Ru‐Bing Wang Dr. Wen Zhou Dr. Qing‐Qing Meng Dr. Xu Zhang Jing Ding Yan Xu Hua‐Long Song Dr. Kai Yang Dr. Jia‐Hua Cui Prof. Shao‐Shun Li |
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Affiliation: | 1. School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 (China);2. Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025 (China) |
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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. |
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Keywords: | alkannin alkylation antitumor agents prodrugs oxidation shikonin |
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