Abstract
The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn(2+) were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylation
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Binding Sites
-
Cell Proliferation / drug effects
-
Chelating Agents / chemical synthesis*
-
Chelating Agents / chemistry
-
Chelating Agents / pharmacology
-
Depsipeptides / chemical synthesis*
-
Depsipeptides / chemistry
-
Depsipeptides / pharmacology
-
Drug Screening Assays, Antitumor
-
HCT116 Cells
-
HeLa Cells
-
Histone Deacetylase Inhibitors / chemical synthesis*
-
Histone Deacetylase Inhibitors / chemistry
-
Histone Deacetylase Inhibitors / pharmacology
-
Histone Deacetylases / metabolism*
-
Humans
-
Isoenzymes / antagonists & inhibitors
-
Isoenzymes / metabolism
-
Stereoisomerism
-
Structure-Activity Relationship
-
Thiazoles / chemical synthesis*
-
Thiazoles / chemistry
-
Thiazoles / pharmacology
-
Zinc / metabolism*
Substances
-
Antineoplastic Agents
-
Chelating Agents
-
Depsipeptides
-
Histone Deacetylase Inhibitors
-
Isoenzymes
-
Thiazoles
-
largazole
-
Histone Deacetylases
-
Zinc