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.
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Authors | Hiroaki Itoh, Masayuki Inoue |
Journal | ACS medicinal chemistry letters
(ACS Med Chem Lett)
Vol. 4
Issue 1
Pg. 52-6
(Jan 10 2013)
ISSN: 1948-5875 [Print] United States |
PMID | 24900563
(Publication Type: Journal Article)
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