title: Dual Chemical Modification of a Polytheonamide Mimic: Rational Design and Synthesis of Ion-Channel-Forming 48-mer Peptides with Potent Cytotoxicity.
abstract: Polytheonamide B (1) is a natural peptide that displays potent cytotoxicity against P388 mouse leukemia cells (IC50=0.098 nm). Linear 48-mer 1 is known to form monovalent cation channels on binding to lipid bilayers. We previously developed a fully synthetic route to 1, and then achieved the design and synthesis of a structurally simplified analogue of 1, namely, dansylated polytheonamide mimic 2. Although the synthetically more accessible 2 was found to emulate the channel function of 1, its cytotoxicity was decreased 120-fold. Herein, the chemical preparation and biological evaluation of seven analogues 3-9 of 2 are reported. Compounds 3-9 were modified at their N terminus and/or the side chain of residue 44 of 2 to alter their physicochemical properties. The total synthesis of 3-9 was accomplished in a unified fashion by a combination of solid-phase and solution-phase chemistry. Systematic evaluation of the hydrophobicities, single-channel currents, ion-exchange activities, and cytotoxicities of 3-9 revealed that their hydrophobicities are correlated with the total magnitude of ion exchange and determine their cytotoxic potency. Consequently, the most hydrophobic analogue 9 exhibited the lowest IC50value, which is comparable to that of 1. Therefore, these results clarified that the bioactivity of the polytheonamide-based peptides can be rationally controlled by changing their hydrophobicity at the N and C termini of the 48-amino-acid sequence.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hayata
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: Shoko
authors.initials: S
authors.lastname: Matsutaka
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. inoue@mol.f.u-tokyo.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
keywords: cytotoxicity; ion channels; peptides; structure-activity relationships; total synthesis