Structural permutation of potent cytotoxin, polytheonamide B: discovery of cytotoxic Peptide with altered activity

Polytheonamide B (1) is an ion-channel forming natural peptide with a d,l-alternating 48 amino acid sequence, which is an exceedingly potent cytotoxin. We recently designed and synthesized a simplified dansylated polytheonamide mimic 2, in which six amino acid residues were modified from 1, and demonstrated that 2 emulated the functions of 1. Here we report a comprehensive structure-activity relationship study of substructures of 2. A unified synthetic strategy was developed for highly automated syntheses of 13 peptide sequences of 27 to 39 amino acid residues, and the artificial 37-mer peptide 6 was discovered to be significantly more toxic than the other 12 compounds toward P388 mouse leukemia cells (IC50 = 3.7 nM). Ion exchange activity experiments of 6 using the liposome and P388 cells both demonstrated that 6 did not possess ion-channel activity, strongly suggesting that 6 exerted its potent cytoxicity through a distinct mode of action from 1 and 2.