In vitro antiproliferative activity of 11-aminoalkylamino-substituted 5H-indolo[2,3-b]quinolines; improving activity of neocryptolepines by installation of ester substituent

The research article describes the effect of an ester group on the in vitro antiproliferative activity in SAR studies of 5-methyl-5H-indolo[2,3-b]quinoline (neocryptolepine) derivatives. The C-2 and/or C-9 ester-substituted neocryptolepines were synthesized starting from indole-3-carboxylates and N-methylanilines, which were bearing an ester group. To these ester-substituted neocryptolepines, various aminoalkylamino substituents were further attached at the C-11, and an in vitro antiproliferative assay was performed by varying the substituents at the C-11 and the position of the ester group in the A and/or D ring of neocryptolepines. Results indicated that the antiproliferative activities of the agents could be improved by introducing an ester substituent at the C-9 position. Among them, the methyl 11-(3-aminopropylamino)-5-methyl-5H-indolo[2,3-b]quinoline-9-carboxylate (8b) was the most potent agent with an IC50 value of 0.044 mu M against the human leukemia MV4-11 cell line. The selective cytotoxicity of the agents between the cancer cell lines and normal cell lines were also described. The antiproliferative potency of dimethyl 11-(3-aminopropylamino)-5-methyl-5H-indolo[2,3-b]quinoline-2,9-dicarboxylate (9a) against the human colon cancer cell line HCT116 is 28 times higher than against the normal mice fibroblast cell line BALB/3T3.