Antitumor activity of arylacetylshikonin analogues

Twenty one phenylacetylshikonin analogues were synthesized from various substituted phenyl acetic acids and their cytotoxicity values against A549, K562 and L1210 cell lines and antitumor action in mice bearing S-180 cells were measured. All of phenylacetylshikonin analogues expressed a potent cytotoxicity (ED₅₀, 0.1–1.80 μg/ml) against L1210 and K562 cells. L 1210 cells were the most sensitive to shikonin analogues among these cells. Except 4-methoxyphenylacetylshikonin (0.098μg/ml) and α-acetoxyphenylacetylshikonin (0.10μg/ml), all other shikonin derivatives showed higher ED₅₀ values than phenylacetylshikonin (0.13μg/ml) in L 1210. In K562 cell, α-substitution of phenylacetylshikonin (0.1 μg/ml), while other substitutions increased it slightly; 4-methoxyphenylacetylshikonin (0.033 μg/ml) showed a exceptionally good cytotoxicity against K562 cell. 4-Halogenation tended to decrease the cytotoxic effect on L1210 cells, while it enhanced the effect on K562; 4-bromophenylacetyl ED₅₀ (L1210)=1.76 μ/ml, ED₅₀ (K 562)=0.32 μg/ml] and 4-chlorophenylacetyl shikonin ED₅₀ (L 1210)=1.64 μg/ml, ED₅₀ (K562)=0.32 μg/ml]. In contrast, A549 cells were much less sensitive to these shikonin analogues which showed ED₅₀ values of 1.5–13.5 μg/ml. Most of phenylacetylshikonin derivatives showed good antitumor activity in mice bearing S-180 cells. α-A-cetoxyphenylacetylshikonin and 4-dimethylaminophenylacetylshikonin showed highest T/C value (192–195%), implying that introduction of α-acetyl or of 4-dimethyl amino group gave a positive effect on the antitumor activity. Introduction of 4-dimethylamino group enhanced the antitumor activity as shown for 4-dimethylaminophenylacetylshikonin (T/C, 192%). It might be due to improvement of water solubility by dimethylamino group in the molecule.