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Total Solid‐Phase Synthesis of the Azathiocoraline Class of Symmetric Bicyclic Peptides
Author(s) -
BayóPuxan Núria,
Fernández Ariadna,
TullaPuche Judit,
Riego Estela,
Cuevas Carmen,
Álvarez Mercedes,
Albericio Fernando
Publication year - 2006
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200600815
Subject(s) - bicyclic molecule , moiety , stereochemistry , combinatorial chemistry , depsipeptide , epimer , chemistry , amide , oxazole , solid phase synthesis , convergent synthesis , peptide , organic chemistry , biochemistry
Thiocoraline is a potent antitumor agent isolated from the marine organism Micromonospora sp. This symmetric bicyclic depsipeptide binds the minor groove of DNA. Here we report two solid‐phase strategies for the syntheses of azathiocoraline and its analogues. The thioester linkage was replaced by an amide bond to improve the compound’s pharmacokinetic properties. The first strategy is based on a convergent (4+4) approach, whilst the second is a stepwise synthesis, cyclizations in both approaches occurring on the solid support. These two strategies were designed to overcome problems caused by the presence of consecutive noncommercial N ‐methyl amino acids, to avoid epimerization during cyclization and/or fragment condensation, and to form the disulfide bridge under solid‐phase conditions. The heterocyclic moiety was added in the last step of the synthesis to assist the preparation of libraries of new compounds with potential therapeutic applications.