Synthesis and antitumour activity of β-hydroxyisovalerylshikonin analogues

A series of novel β-hydroxyisovalerylshikonin analogues bearing oxygen-containing substituents at the side-chain hydroxyl of shikonin were designed and synthesized. The cytotoxicities of these compounds were evaluated in vitro against multi-drug resistant (MDR) cell lines DU-145 and HeLa. Most compounds exhibited significant inhibitory activity on both cell lines. The structure–activity relationship showed the analogues with ether substituents displayed the most potent antitumour activity and selective cytotoxicity towards DU-145. Among the compounds with ether substituents, increasing the steric hindrance in the carbon bearing β-hydroxyl or replace the β-hydroxyl with acetoxy or methoxy would lead to the decline of cytotoxicity.

Graphical abstractA series of novel β-hydroxyisovalerylshikonin analogues were synthesized and tested for cytotoxicity in vitro. Most compounds exhibited significant inhibitory activity, and SAR study was also carried out.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel β-HIVS analogues with oxygen-containing substituents were synthesized. ► They were tested for cytotoxicity and exhibited significant antitumour activity. ► The introduction of oxygen-containing substituents to shikonin was a success.