The total synthesis and functional evaluation of fourteen stereoisomers of yaku'amide B. The importance of stereochemistry for hydrophobicity and cytotoxicity.
Yaku'amide B is a highly unsaturated linear tridecapeptide and an extremely potent cytotoxin. Herein, we describe the synthesis of fourteen new stereoisomers of yaku'amide B using a unified assembly strategy. The hydrophobicities and cytotoxicities of these analogues were analyzed, along with those of four previously prepared isomers. Although all of the analogues share a common planar structure, their log D values varied significantly (3.39-5.32), presumably reflecting their distinct three-dimensional shapes. Subnanomolar-level cytotoxicity was observed for the natural yaku'amide B and its epimer of the N-terminal acyl group, whereas the other sixteen isomers exhibited 13- to 1200-fold weaker activities than that of the natural isomer. These data indicated the importance of the overall stereostructure of the 13-mer sequence of yaku'amide B for exerting its potent toxicity.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. inoue@mol.f.u-tokyo.ac.jp.
Hiroyuki
H
Mutoh
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. inoue@mol.f.u-tokyo.ac.jp.
Yusuke
Y
Sesoko
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. inoue@mol.f.u-tokyo.ac.jp.
Takefumi
T
Kuranaga
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. inoue@mol.f.u-tokyo.ac.jp.
Hiroaki
H
Itoh
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. inoue@mol.f.u-tokyo.ac.jp.
Masayuki
M
Inoue
D000818:Animals; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D013237:Stereoisomerism
D003603:Cytotoxins; D009842:Oligopeptides; C556701:yaku'amide B