1. The first total synthesis of the cyclodepsipeptide pipecolidepsin A.
- Author
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Pelay-Gimeno M, García-Ramos Y, Jesús Martin M, Spengler J, Molina-Guijarro JM, Munt S, Francesch AM, Cuevas C, Tulla-Puche J, and Albericio F
- Subjects
- Animals, Cell Line, Tumor, Depsipeptides chemical synthesis, Depsipeptides chemistry, Female, HT29 Cells, Hep G2 Cells, Humans, MCF-7 Cells, Male, Pipecolic Acids chemical synthesis, Pipecolic Acids chemistry, Porifera metabolism, Structure-Activity Relationship, Depsipeptides pharmacology, Neoplasms drug therapy, Pipecolic Acids pharmacology
- Abstract
Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered γ-branched β-hydroxy-α-amino acid D-allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D-allo-Thr and L-pipecolic acid. Here we describe the first total synthesis of a D-allo-AHDMHA-containing peptide, pipecolidepsin A, thus allowing chemical structure validation of the natural product and providing a robust synthetic strategy to access other members of the relevant head-to-side-chain family in a straightforward manner.
- Published
- 2013
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