• Archives of Pharmacal Research
• /
• v.20 no.2
• /
• pp.155-157
• /
• 1997

An attempt to estabilish the relationship between anti-cell adhesive action of phenylacetylshikonin analogues and their cytotoxicity against A549 cells was done. In the one hour incubation with A549 cells,${\alpha}$-methoxyphenylacetyl-(9), ${\alpha}$-acetoxyphenylacetyl-(13), 3,4-methylenedioxyphenylacetyl-(15) and 4-(N,N-dimethylamino)-phenylacetylshikonin (17) analogues showed a high anti-cell adhesive activity $(IC_100; value, 4-8{\mu}g/ml)$, while halophenylacetyl- and dimethoxy- or trimethoxyphenylacetyl analogues expressed no activity at $40{\mu}g/ml$, indicating that the presence of a bulky group at $ C^I-{\alpha}$ and a polar group at C-4 of phenylacetyl moiety may be important. A similar structure activity relationship exists for the 48 hr cytotoxocity $(ED_{50})$ of phenylacetylshikonin analogues in A 549 cells, but not in either K562 or L1210 cells. Furthermore, the difference between $IC_{100}$ values for anti-cell adhesive activity and$ED_{50}$ values for cytotoxicity of potent compound in A549 cells was not so great (1.5 to 3 times). Based on these observations, it is proposed that the anti-cell adhesive action of phenylacetylshikonins might be responsible for their cytotoxicity in A549 cells.

• Archives of Pharmacal Research
• /
• v.19 no.5
• /
• pp.416-422
• /
• 1996

Twenty one phenylacetylshikonin analogues were synthesized from various subsitituted 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 $(ED_{50}, 0.1-1.80{\mu}g/ml)$ against L1210 and K562 cells. L1210 cells were the most sensitive to shikonin analogues among these cells. Except 4-methosyphenylacetylshikonin $(0.098 {\mu}g/ml)$, and a-acetoxyphenylacetylshikonin $(0.10 {\mu}g/ml)$, all other shikonin derivatives sshowed higher $ED_{50}$ values than phenylacetylshikonin $(0.13{\mu}g/ml)$, in L1210. In K562 cell, a-substitution of phenylacetylshikonin $(0.1{\mu}g/ml)$, while other subsitutions increased it slightly; 4-methoxyphenylacetylshikonin $(0.033{\mu}g/ml)$ 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 $$[ED_{50};(L1210)=1.76{\mu}g/ml, ;ED_{50};(K 562)=0.32 {\mu}g/ml]$$ and 4-chlorophenylacetyl shikonin $$[ED_{50};(L1210)=1.64 {\mu}g/ml, ;ED_{50};(K562)=0.32 {\mu}g/ml]$$. In contrast, A549 cells were much less sensitive to these shikonin analogues which showed $ED_{50}$ values of$1.5-1.35 {\mu}g/ml)$.Most of phenylacetylshikonin derivatives showed good antitumor activity in mice bearing S-180 cells. a-A-cetoxyphenylacetylshikonin and 4-dimethylaminophenylacetylshikonin showed highest T/C value (192-195%), implying that introduction of a-acetyl or 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.