Abstract
A new class of small molecules, with an unprecedented trifluorothiazoline scaffold, were synthesized and their pro-apoptotic activity was evaluated. With an EC50 in the low micromolar range, these compounds proved to be potent inducers of apoptosis in a broad spectrum of tumor cell lines, regardless of the functional status of p53. Fast structure-activity relationship studies allowed the preparation of the strongest apoptosis-inducing candidate. Using a high performance affinity purification approach, we identified prohibitins 1 and 2, key proteins involved in the maintenance of cell viability, as the targets for these compounds.
Keywords:
antitumor agents; drug discovery; fluorine; heterocycles; medicinal chemistry.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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HeLa Cells
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Humans
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Hydrocarbons, Fluorinated / chemical synthesis
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Hydrocarbons, Fluorinated / chemistry
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Hydrocarbons, Fluorinated / pharmacology*
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Jurkat Cells
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Molecular Structure
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Prohibitins
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Repressor Proteins / antagonists & inhibitors*
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Repressor Proteins / metabolism
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / chemistry
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Thiazoles / pharmacology*
Substances
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Antineoplastic Agents
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Hydrocarbons, Fluorinated
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Prohibitins
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Repressor Proteins
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Thiazoles