Document Detail


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.
MedLine Citation:
PMID:  19760730     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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, (3S or 3R,4E)-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 nM) over class II HDAC6 (IC(50)=3900 nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC(50) values.
Authors:
Koichi Narita; Takuya Kikuchi; Kazuhiro Watanabe; Toshiya Takizawa; Takamasa Oguchi; Kyosuke Kudo; Keisuke Matsuhara; Hideki Abe; Takao Yamori; Minoru Yoshida; Tadashi Katoh
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemistry (Weinheim an der Bergstrasse, Germany)     Volume:  15     ISSN:  1521-3765     ISO Abbreviation:  Chemistry     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-11-30     Completed Date:  2010-02-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9513783     Medline TA:  Chemistry     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  11174-86     Citation Subset:  IM    
Affiliation:
Laboratory of Synthetic Medicinal Chemistry, Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemical synthesis*,  chemistry,  pharmacology
Cell Line, Tumor
Depsipeptides / chemical synthesis*,  chemistry,  pharmacology
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors / chemical synthesis*,  chemistry,  pharmacology
Histone Deacetylases / chemistry*,  metabolism
Humans
Peptides, Cyclic / chemical synthesis*,  chemistry,  pharmacology
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Depsipeptides; 0/Histone Deacetylase Inhibitors; 0/Peptides, Cyclic; 0/spiruchostatin A; 0/spiruchostatin B; 128517-07-7/romidepsin; EC 3.5.1.98/Histone Deacetylases

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