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Total Synthesis of the Bicyclic Depsipeptide HDAC Inhibitors Spiruchostatins A and B, 5′′‐ epi ‐Spiruchostatin B, FK228 (FR901228) and Preliminary Evaluation of Their Biological Activity
Author(s) -
Narita Koichi,
Kikuchi Takuya,
Watanabe Kazuhiro,
Takizawa Toshiya,
Oguchi Takamasa,
Kudo Kyosuke,
Matsuhara Keisuke,
Abe Hideki,
Yamori Takao,
Yoshida Minoru,
Katoh Tadashi
Publication year - 2009
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.200901552
Subject(s) - depsipeptide , stereochemistry , chemistry , bicyclic molecule , histone deacetylase , histone deacetylase inhibitor , biochemistry , histone , gene
The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5′′‐ epi ‐spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps: i) a Julia–Kocienski olefination of a 1,3‐propanediol‐derived sulfone and a L ‐ or D ‐malic acid‐derived aldehyde to access the most synthetically challenging unit, (3 S or 3 R ,4 E )‐3‐hydroxy‐7‐mercaptohept‐4‐enoic acid, present in a D ‐alanine‐ or D ‐valine‐containing segment; ii) a condensation of a D ‐valine‐ D ‐cysteine‐ or D ‐ allo ‐isoleucine‐ D ‐cysteine‐containing segment with a D ‐alanine‐ or D ‐valine‐containing segment to directly assemble the corresponding seco ‐acids; and iii) a macrocyclization of a seco ‐acid using the Shiina method or the Mitsunobu method to construct the requisite 15‐ or 16‐membered macrolactone. The present synthesis has established the C5′′ stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell‐growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure–activity relationships. It was also found that unnatural 5′′‐ epi ‐spiruchostatin B shows extremely high selectivity (ca. 1600‐fold) for class I HDAC1 (IC 50 =2.4 n M ) over class II HDAC6 (IC 50 =3900 n M ) with potent cell‐growth‐inhibitory activity at nanomolar levels of IC 50 values.