title: Potent oxazoline analog of apratoxin C: Synthesis, biological evaluation, and conformational analysis.
abstract: In this research, the synthesis, biological evaluation, and conformational analysis of an apratoxin C oxazoline analog (3) have been demonstrated. The preparation of synthetic key intermediate 9 was achieved using an improved strategy that involves commercially available 3-methylglutaric anhydride (12), an enzymatic enantioselective alcoholysis, and a diastereoselective reduction. The Pro-Dtrina (3,7-dihydroxy-2,5,8-trimethylnonanoic acid) moiety 8 was successfully synthesized in a similar manner as our previously reported synthesis of apratoxin C (1). The cyclization precursor 5 was formed after the coupling of Pro-Dtrina 8 with a known tetrapeptide 7 to afford a linear peptide 6, the formation of an oxazoline, and the removal of the protecting groups. Finally, the macrolactamization of 5 with O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)/N,N-diisopropylethylamine (DIEA) furnished an apratoxin C oxazoline analog (3), which exhibited a potent cytotoxicity against HeLa cells (IC50 value of 22 nM) that was comparable with the cytotoxicity of apratoxin C (1) (IC50 value of 4.2 nM). Conformational analyses of 1 and 3 through NMR experiments showed that oxazoline analog 3 formed a tertiary structure that was similar to the apratoxin C (1) structure in CD3 CN, which provided a probable explanation for their comparable cytotoxicities. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 404-414, 2016.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan.|Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda-Shi, Saitama, 335-8505, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Onda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Masuda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Doi
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans
chemical_list: D003603:Cytotoxins; D047630:Depsipeptides; C470919:apratoxin C
keywords: apratoxin; conformational analysis; cyclodepsipeptide; natural product; total synthesis