An improved and practical synthesis route to antiproliferative (±)-shikonin and its O-acyl derivatives

Abstract

Shikonin and its O-acyl derivatives are attracting increasing levels of attention among medicinal chemists due to their potencies as highly selective cytotoxic agents against cancer cells. However, providing a large number of shikonin-related samples by organic synthesis remains challenging. In the present study, we developed an improved and practical synthesis route to shikonin derivatives by olefin metathesis that has enabled the gram-scale preparation of a prenylated tetramethylnaphthazaline, a key intermediate in the synthesis of shikonin. In addition, a method for the selective cleavage of the acyl protecting groups at the phenolic positions of tri-O-acylated shikonins has been developed that provides concise routes to diverse O-acylshikonin derivatives.

Graphical Abstract

Keywords:

• Shikonin
• O-acyl shikonin
• gram-scale synthesis
• olefin metathesis

Acknowledgement

The authors would like to thank Editage (www.editage.jp) for English language editing.

Additional information

Funding

This research was partially supported by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities at Toho University, 2012–2016 [S1201034].