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Synthesis and Biological Characterization of the Histone Deacetylase Inhibitor Largazole and C7- Modified Analogues
- Source :
- Journal of Medicinal Chemistry. 53:4654-4667
- Publication Year :
- 2010
- Publisher :
- American Chemical Society (ACS), 2010.
-
Abstract
- Largazole 4a and analogues with modifications at the C7 position, as well as 2,4'-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides 4b-d, but not 2,4'-bithiazole 5a, showed a marked inhibition of recombinant HDAC1 and selectivity over HDAC4, as well as strong pro-apoptotic effects on the NB4 leukemia cell line, but they failed to induce differentiation to mature granulocytes. Functional assays of the analogues correlated with the in vitro activities, as shown by increased H3 and alpha-tubulin acetylation levels and p21(WAF1/CIP1) up-regulation in NB4 cells. The activity of the natural product HDACi largazole 4a is not significantly altered by the presence of groups of different size (H, Et, Ph) at C7 on the dihydrothiazole ring.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
Stereochemistry
medicine.drug_class
Antineoplastic Agents
Apoptosis
Histone Deacetylase 1
Histone Deacetylases
Structure-Activity Relationship
chemistry.chemical_compound
Tubulin
Cell Line, Tumor
Depsipeptides
Drug Discovery
medicine
Humans
Depsipeptide
Natural product
Histone deacetylase inhibitor
Acetylation
Cell Differentiation
Stereoisomerism
HDAC4
Recombinant Proteins
In vitro
HDAC1
CD11c Antigen
Histone Deacetylase Inhibitors
Repressor Proteins
Thiazoles
chemistry
Biochemistry
Lactam
Molecular Medicine
Drug Screening Assays, Antitumor
Granulocytes
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 53
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....cbc665f396400282489cceb138b7a7fc