ABSTRACT
A series of suberoylanilide hydroxamic acid (SAHA)-based non-hydroxamates was designed, synthesized, and evaluated for their histone deacetylase (HDAC) inhibitory activity. Among these, methyl sulfoxide 15 inhibited HDACs in enzyme assays and caused hyperacetylation of histone H4 while not inducing the accumulation of acetylated alpha-tubulin in HCT116 cells.
Subject(s)
Acetylation/drug effects , Drug Design , Enzyme Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors , Histone Deacetylases/metabolism , Hydroxamic Acids/chemical synthesis , Cell Proliferation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , HCT116 Cells , Histone Deacetylases/chemistry , Histones/metabolism , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Structure-Activity Relationship , Tubulin Modulators , VorinostatABSTRACT
To find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) was designed and synthesized. In this series, compound 7, in which the hydroxamic acid of SAHA is replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. In cancer cell growth inhibition assay, S-isobutyryl derivative 51 showed strong activity, and its potency was comparable to that of SAHA. The cancer cell growth inhibitory activity was verified to be the result of histone hyperacetylation and subsequent induction of p21(WAF1/CIP1) by Western blot analysis. Kinetical enzyme assay and molecular modeling suggest the thiol formed by enzymatic hydrolysis within the cell interacts with the zinc ion in the active site of HDACs.
Subject(s)
Antineoplastic Agents/chemical synthesis , Histone Deacetylase Inhibitors , Hydroxamic Acids/chemical synthesis , Thiazoles/chemical synthesis , Acetylation , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Binding, Competitive , Cell Cycle Proteins/biosynthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p21 , Drug Screening Assays, Antitumor , Histone Deacetylases/chemistry , Histones/metabolism , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Models, Molecular , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , VorinostatABSTRACT
In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, we synthesized several suberoylanilide hydroxamic acid (SAHA)-based compounds designed on the basis of the catalytic mechanism of HDACs. Among these compounds, 5b was found to be as potent as SAHA. Kinetic enzyme assays and molecular modeling suggested that the mercaptoacetamide moiety of 5b interacts with the zinc in the active site of HDACs and removes a water molecule from the reactive site of the deacetylation.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors , Hydroxamic Acids/chemical synthesis , Acetamides/chemistry , Acetylation , Binding Sites , Enzyme Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Kinetics , Models, Molecular , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Vorinostat , Zinc/chemistryABSTRACT
In order to find novel nonhydroxamate histone deacetylase (HDAC) inhibitors, a series of thiol-based compounds modeled after suberoylanilide hydroxamic acid (SAHA) was synthesized, and their inhibitory effect on HDACs was evaluated. Compound 6, in which the hydroxamic acid of SAHA was replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA.
Subject(s)
Enzyme Inhibitors/chemistry , Histone Deacetylase Inhibitors , Hydroxamic Acids/chemistry , Sulfhydryl Compounds/chemistry , Enzyme Inhibitors/pharmacology , Histone Deacetylases/metabolism , Hydroxamic Acids/pharmacology , Sulfhydryl Compounds/pharmacology , VorinostatABSTRACT
In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) were designed and synthesized as (i). substrate (acetyl lysine) analogues (compounds 3-7), (ii). analogues bearing various functional groups expected to chelate zinc ion (compounds 8-15), and (iii). analogues bearing nucleophilic functional groups which could bind covalently to HDACs (compounds 16-18). In this series, semicarbazide 8b and bromoacetamides 18b,c were found to be potent HDAC inhibitors for non-hydroxamates.