Total synthesis of the large non-ribosomal peptide polytheonamide B.
Polytheonamide B is by far the largest non-ribosomal peptide known at present, and displays extraordinary cytotoxicity (EC(50) = 68 pg ml(-1), mouse leukaemia P388 cells). Its 48 amino-acid residues include a variety of non-proteinogenic d- and l-amino acids, and the absolute stereochemistry of these amino acids alternate in sequence. These structural features induce the formation of a stable β-strand-type structure, giving rise to an overall tubular structure over 30 Å in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. Here, we report the first chemical construction of polytheonamide B. Our synthesis relies on the combination of four key stages: syntheses of non-proteinogenic amino acids, a solid-phase assembly of four fragments of polytheonamide B, silver-mediated connection of the fragments and, finally, global deprotection. The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.
The University of Tokyo, Tokyo 113-0033, Japan. inoue@mol.f.u-tokyo.ac.jp
Masayuki
M
Inoue
Naoki
N
Shinohara
Shintaro
S
Tanabe
Tomoaki
T
Takahashi
Ken
K
Okura
Hiroaki
H
Itoh
Yuki
Y
Mizoguchi
Maiko
M
Iida
Nayoung
N
Lee
Shigeru
S
Matsuoka
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D005449:Fluorenes / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry; D011506:Proteins / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D012451:Safrole / Q000031:analogs & derivatives / Q000737:chemistry; D013237:Stereoisomerism
C496789:9-fluorenylmethoxycarbonyl; D000970:Antineoplastic Agents; D005449:Fluorenes; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D011506:Proteins; C111717:polytheonamide B; D012451:Safrole; C005746:sulfoxide