Details

Autor(en) / Beteiligte

• Wang, Ru-Bing
• Zhou, Wen
• Meng, Qing-Qing
• Zhang, Xu
• Ding, Jing
• Xu, Yan
• Song, Hua-Long
• Yang, Kai
• Cui, Jia-Hua
• Li, Shao-Shun

Titel

Design, Synthesis, and Biological Evaluation of Shikonin and Alkannin Derivatives as Potential Anticancer Agents via a Prodrug Approach

Ist Teil von

• ChemMedChem, 2014-12, Vol.9 (12), p.2798-2808

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. The A‐B‐Cs of a prodrug strategy: Group B compounds show good selectivity and low ROS generation and alkylation in vitro. Acetylation of B results in dimethylated diacetyl derivatives C. Like typical prodrugs, group C compounds exhibit no cytotoxicity in vitro, but show tumor inhibition effects akin to the non‐acylated analogues B, without in vivo toxicity. Metabolism by rat liver microsomes suggests that group C compounds are indeed prodrugs of group B.