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Dual Chemical Modification of a Polytheonamide Mimic: Rational Design and Synthesis of Ion‐Channel‐Forming 48‐mer Peptides with Potent Cytotoxicity
Author(s) -
Hayata Atsushi,
Itoh Hiroaki,
Matsutaka Shoko,
Inoue Masayuki
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201504632
Subject(s) - chemistry , cytotoxicity , peptide , stereochemistry , ion channel , rational design , chemical synthesis , combinatorial chemistry , chemical modification , ic50 , in vitro , biochemistry , nanotechnology , receptor , materials science
Polytheonamide B ( 1 ) is a natural peptide that displays potent cytotoxicity against P388 mouse leukemia cells (IC 50 =0.098 n m ). 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 IC 50 value, 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.