ANTITUMOR-ACTIVITY OF ARYLACETYLSHIKONIN ANALOGS

Twenty one phenylacetylshikonin analogues were synthesized from variou s substituted phenyl acetic acids and their cytotoxicity values agains t A549, K562 and L1210 cell lines and antitumor action in mice bearing S-180 cells were measured. All of phenylacetylshikonin analogues expr essed a potent cytotoxicity (ED(50) 0.1-1.80 mu g/ml) against L1210 an d K562 cells. L 1210 cells were the most sensitive to shikonin analogu es among these cells. Except 4-methoxyphenylacetylshikonin (0.098 mu g / ml) and alpha-acetoxyphenylacetylshikonin (0.10 mu g/ml), all other shikonin derivatives showed higher ED(50) values than phenylacetylshik onin (0.13 mu g/ml) in L 1210. In K562 cell, alpha-substitution of phe nylacetylshikonin (0.1 mu g/ml), while other substitutions increased i t slightly; 4-methoxyphenylacetylshikonin (0.033 mu g/ml) showed a exc eptionally 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 [ED(50) (L1210)=1.76 mu g/ml, ED( 50) (K 562)=0.32 mu g/ml] and 4-chlorophenylacetyl shikonin [ED(50) (L 1210)=1.64 mu g/ml, ED(50) (K562)=0.32 mu g/ml]. In contrast, A549 ce lls were much less sensitive to these shikonin analogues which showed ED(50) values of 1.5-13.5 mu g/ml. Most of phenylacetylshikonin deriva tives showed good antitumor activity in mice bearing S-180 cells. alph a-A-cetoxyphenylacetylshikonin and 4-dimethylaminophenylacetylshikonin showed highest T/C value (192-195%), implying that introduction of al pha-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-dimethylaminophenlylacetylshikonin (T/C, 192%). It might be due to improvement of water solubility by dim ethylamino group in the molecule.