Abstract
The transducing ability of the third helix of transcription factor homeodomains is effectively mimicked by a biphenyl system displaying guanidine groups. The biphenyl class of small molecule carriers (SMoCs) can carry biomolecules into a wide variety of cell types. A "combinatorial" approach to the synthesis of SMoCs is described using sequential Pd(0) coupling chemistry to assemble the molecules from highly functionalized building blocks. SMoCs coupled to the DNA licensing repressor protein geminin can inhibit DNA replication in vitro. We conducted a structure-activity investigation utilizing a range of SMoC-geminin conjugates and demonstrate that both electrostatic and structural features are important for efficient uptake and functional activity. The best analogue was more efficient than either (Arg)(4) or (Arg)(8) linked to geminin. Effective inhibition of DNA synthesis was achieved in fibroblasts and osteosarcoma cell lines.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arginine / chemistry
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Benzene / chemistry
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Biomimetic Materials / chemical synthesis*
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Biomimetic Materials / chemistry
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Biomimetic Materials / metabolism
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Biomimetic Materials / pharmacology*
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Biphenyl Compounds / chemical synthesis*
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / metabolism
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Biphenyl Compounds / pharmacology*
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism
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Cell Line
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Cells / metabolism*
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DNA Replication / drug effects
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Flow Cytometry
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Humans
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Hydrocarbons, Halogenated / chemistry
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Nucleic Acid Synthesis Inhibitors / chemical synthesis
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Nucleic Acid Synthesis Inhibitors / chemistry
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Nucleic Acid Synthesis Inhibitors / metabolism
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Palladium / chemistry*
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Static Electricity
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Structure-Activity Relationship
Substances
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Biphenyl Compounds
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Cell Cycle Proteins
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Hydrocarbons, Halogenated
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Nucleic Acid Synthesis Inhibitors
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Palladium
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Arginine
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Benzene