Control of the cytotoxicity of dansylated polytheonamide mimic, an artificial peptide ion channel, by modification of the N-terminal structure

•Polytheonamide B is an ion channel forming peptide that displays potent cytotoxicity.•Dansylated polytheonamide mimic was designed as its simplified analogue.•The three analogues of the mimic were synthesized and biologically evaluated.•A 10-fold enhancement in the cytotoxicity was attained by increasing the log P value.•The data provide new understanding for the functional control of the ion channel.

We demonstrate that the cytotoxicity of dansylated polytheonamide mimic (2) is controlled by chemical modification of its N-terminal structure. Dansylated polytheonamide mimic (2) is an ion channel peptide which displays potent cytotoxicity against P388 mouse leukemia cells (IC50 = 12 nM). To modulate its cytotoxicity, three analogues of 2, possessing distinct N-terminal structures with different hydrophobicities, were synthesized and their cytotoxicities were evaluated. This focused structure-activity relationship study unveiled that the cytotoxicity of 2 is enhanced 10-fold by simply changing its N-terminal 5,5-dimethyl-2-oxohexanamide to the more hydrophobic palmitamide. The data obtained here provide new understanding for the functional control of the artificial ion channel peptide 2.

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