title: Structural permutation of potent cytotoxin, polytheonamide B: discovery of cytotoxic Peptide with altered activity.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo , Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo , Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
keywords: Cytotoxic agents; natural products; solid-phase synthesis; structure−activity relationships; synthetic ion channels