ABSTRACT
To uncover novel histone deacetylase 6 (HDAC6)-selective inhibitors and to elucidate the structural requirements for their inhibitory activity, we designed and prepared a series of thiolate analogues based on the structure of an HDAC6-selective substrate and evaluated their properties by Western blotting and enzyme assays. Several thiolate analogues were found to be potent and selective HDAC6 inhibitors. Study of the structure-selectivity relationship revealed that the presence of a bulky alkyl group and tert-butylcarbamate group in these compounds is important for HDAC6-selective inhibition. Compounds 16b and 20b, the most selective and active compounds in this series, exerted a synergistic inhibition of cancer cell growth in combination with paclitaxel. They also blocked the growth of estrogen receptor alpha-positive breast cancer MCF-7 cells that had been treated with estrogen. These findings suggested that HDAC6-selective inhibitors have potential as anticancer agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carbamates/chemical synthesis , Histone Deacetylase Inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , Drug Screening Assays, Antitumor , Drug Synergism , Histone Deacetylase 6 , Histone Deacetylases , Humans , Paclitaxel/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
To find novel histone deacetylase 6 (HDAC6)-selective inhibitors and clarify the structural requirements for HDAC6-selective inhibition, we prepared thiolate analogues designed based on the structure of an HDAC6-selective substrate and evaluated the histone/alpha-tubulin acetylation selectivity by Western blot analysis. Aliphatic compounds 17b-20b selectively caused alpha-tubulin acetylation over histone H4 acetylation. In enzyme assays using HDAC1, HDAC4, and HDAC6, compounds 17a-19a exhibited HDAC6-selective inhibition over HDAC1 and HDAC4.
Subject(s)
Histone Deacetylase Inhibitors , Sulfhydryl Compounds/chemical synthesis , Acetylation , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , HCT116 Cells , Humans , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacology , Tubulin/metabolismABSTRACT
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.
