Abstract
A strategy to develop chemotherapeutic agents by combining several active groups into a single molecule as a conjugate that can modulate multiple cellular pathways may produce compounds having higher efficacy compared to that of single-target drugs. In this article, we describe the synthesis and evaluation of an array of dual-acting ER and histone deacetylase inhibitors. These novel hybrid compounds combine an indirect antagonism structure motif of ER (OBHS, oxabicycloheptene sulfonate) with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). These OBHS-HDACi conjugates exhibited good ER binding affinity and excellent ERα antagonistic activity, and they also exhibited potent inhibitory activities against HDACs. Compared with the approved drug tamoxifen, these conjugates exhibited higher antitumor potency in ERα-positive breast cancer cells (MCF-7). Moreover, these conjugates not only showed selective anticancer activity that was more potent against MCF-7 cells than DU 145 (prostate cancer), but they had no toxicity toward normal cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents, Hormonal / pharmacology
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Antineoplastic Combined Chemotherapy Protocols
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Arylsulfonates / chemistry
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Arylsulfonates / pharmacology*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / pathology
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Bridged Bicyclo Compounds / chemistry
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Bridged Bicyclo Compounds / pharmacology*
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Cell Proliferation / drug effects
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Estrogen Receptor alpha / antagonists & inhibitors*
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Estrogen Receptor alpha / metabolism
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Female
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / chemistry*
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Histone Deacetylases / metabolism
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Humans
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Models, Molecular
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Molecular Structure
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Structure-Activity Relationship
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Tamoxifen / pharmacology
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Antineoplastic Agents, Hormonal
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Arylsulfonates
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Bridged Bicyclo Compounds
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ESR1 protein, human
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Estrogen Receptor alpha
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Histone Deacetylase Inhibitors
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Tamoxifen
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Histone Deacetylases