Syntheses and structure–activity relationships in cytotoxicities of 13-substituted quaternary coptisine derivatives

•Twenty five 13-substituted quaternary coptisine derivatives were synthesized.•Introduction of alkyls into 13-position led to significant increases of cytotoxicity.•Extending the alkyl side chain increased the cytotoxic activity.•Aromaric methyl and analogs of arylmethyls causes cytotoxicity on IEC-6.•Introducing other arylmethyls into 13-position showed no effect on tested activity.

Twenty five 13-substituted quaternary coptisine derivatives were synthesized to test their cytotoxicities against several cancer cell-lines and on intestinal epithelial cell-6 (IEC-6) in vitro to evaluate structure–activity relationship (SAR). Introduction of the alkyl groups into the C-13 position of quaternary coptisine (1) led to significant increase of the cytotoxic activity, while the substitution of arylmethyl groups and others at the same position showed no effect on improving cytotoxicities against the same cancer cell-lines. The cytotoxicities of quaternary 13-alkylcoptisines was significantly reinforced as the length of the aliphatic chain increased, with quaternary 13-n-undecylcoptisine (4l) showing 7, 23, 12, and 9 times, respectively, more active than quaternary coptisine (1) against HCT, A549, Bel7402, and C33A, and being 4, 11, 2, and 3 times, respectively, more active than the positive control, fluorouracil (5-FU), against the same cell-lines, by IC50 values. In comparison to quaternary 13-n-undecylcoptisine (4l) and the above references, quaternary 13-n-dodecylcoptisine (4m) almost showed the same cytotoxicities. In contrast with the n-alkyl chains, the arylmethyl substituents at C-13 displayed low cytotoxicity, except for naphthyl rings or phenyl rings with CF3 or methyl substituents. However, their low cytotoxicity could make them useful as drug candidates for other diseases (bowel, etc).

Graphical abstractTwenty five 13-substituted quaternary coptisine derivatives were synthesized and tested for their cytotoxicity to evaluate the structure–activity relationships, with explicit influencing factor on improving activity being obtained.Figure optionsDownload full-size imageDownload as PowerPoint slide