POTENTIAL ANTILEUKEMIC AGENTS, SYNTHESIS OF DERIVATIVES OF INDIRUBIN, INDIGO, AND ISOINDIGOTIN

Indirubin is used clinically for the treatment of chronic granulocytic leukemic in China. Our previous paper reported the syntheses of N₁′substituted derivatives of indirubin.In an attempt to study the role of N₁-substitution and connecting position of two indole rings in the antitumor activity, two N₁-substituted and one N₁N₁, -bissubstituted derivatives of indirubin (Ⅰ₁, Ⅰ₂, Ⅰ₃), and six bisindolinones, derivatives of indigo and isoindigotin (Ⅱ_1～3, Ⅲ_1～3) were synthesized.In the. preparation of compounds Ⅰ_1～3 from N-alkyl-O-acetyl indoxyl Ⅳ (R=-CH₃ or -C₂H₅) with isatin or N-methylisatin, the self-condensation of the indoxyl to N-substituted indigo is suppressed by using strong acid, p-toluenesulfonic acid as condensing catalyst. It has been suggested that aminium formation stabilizes the indoxyl compound thus inhibits the self-condensation and facilitates the desired condensation of indoxyl with isatin to give a yield of 60%. Treatment of indigo with equimolecular quantity of sodium hydride, followed by corresponding alkyl halides, gave compounds Ⅱ_1～3. Isoindigotin series compunds Ⅲ_1～3 were obtained by condensation of the oxindole with corresponding N-alkylisatin.The lipid soluble N-ethyl indigo and N-methyl or N-ethyl isoindigotin exhibit inhibitory action on Walker carcinoma 256 against which their parent compounds are inactive. Substitution on N₁-position of indirubin caused loss of activity, but N₁N₁, -dimethylindirubin (Ⅰ₃) exhibits certain anticancer activity.