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Total Synthesis of the Depsipeptide FR901375 and Preliminary Evaluation of Its Biological Activity
Author(s) -
Narita Koichi,
Katoh Yuya,
Ojima Kenichi,
Dan Singo,
Yamori Takao,
Ito Akihiro,
Yoshida Minoru,
Katoh Tadashi
Publication year - 2016
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201601023
Subject(s) - depsipeptide , romidepsin , chemistry , histone deacetylase , stereochemistry , bicyclic molecule , total synthesis , histone deacetylase inhibitor , valine , cysteine , amino acid , biochemistry , histone , enzyme , gene
The bicyclic depsipeptide FR901375 was efficiently synthesized in a highly convergent manner. The synthesis involved the condensation of a d ‐valine– d ‐valine– d ‐cysteine‐containing segment with a (3 S ,4 E )‐3‐hydroxy‐7‐mercapto‐4‐heptenoic acid– l ‐threonine‐containing segment to directly assemble the corresponding seco ‐amino acid, followed by cyclization to construct the desired 16‐membered macrocyclic ring. The potency of the synthesized FR901375 was determined in assays for histone deacetylase (HDAC) inhibition and cell‐growth inhibition, and the results were compared to those obtained for the clinically approved depsipeptide FK228 (romidepsin). It was found that FR901375 shows extremely high selectivity (957‐fold) for a class I HDAC 1 (GI 50 = 1.7 n m ) over a class II HDAC 6 (GI 50 = 1627 n m ), and shows cell‐growth inhibition GI 50 values in the low nanomolar region. Furthermore, new aspects of the structure–activity relationship of bicyclic depsipeptide HDAC inhibitors were revealed.