Synthesis and biological evaluation of heterocyclic carboxylic acyl shikonin derivatives.

A series of shikonin derivatives (1-13) that were acylated selectively by various thiophene or indol carboxylic acids at the side chain of shikonin were synthesized, and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3 ((R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 3-(1H-indol-3-yl)propanoate) and compound 8 ((R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(thiophen-3-yl)acetate) exhibited good antiproliferative activity of A875 (IC50=0.005 +/- 0.001m, 0.009 +/- 0.002m) and HeLa (IC50=11.84 +/- 0.64m, 4.62 +/- 0.31m) cancer cell lines in vitro, respectively. Shikonin (IC50=0.46 +/- 0.002m, 4.80 +/- 0.48m) and colchicine (IC50=0.75 +/- 0.05m, 17.79 +/- 0.76m) were used as references. Meanwhile, they also showed the most potent growth inhibitory activity against tubulin (IC50 of 3.96 +/- 0.13m and 3.05 +/- 0.30m, respectively), which were compared with shikonin (IC50= 15.20 +/- 0.25m) and colchicine (IC50=3.50 +/- 0.35 m). Furthermore, from the results of flow cytometer, we found compound 3 can really inhibit HeLa cell proliferation and has low cell toxicity. Based on the preliminary results, compound 3 with potent inhibitory activity in tumor growth may be a potential anticancer agent.