Modular assembly using sequential palladium coupling gives easy access to the SMoC class of cellular transporters.
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.
Rebstock
Anne-Sophie
AS
Biological and Medicinal Chemistry Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT UK.
Visintin
Cristina
C
Leo
Elisabetta
E
Garcia Posada
Cristina
C
Kingsbury
Sarah R
SR
Williams
Gareth H
GH
Stoeber
Kai
K
Selwood
David L
DL
D001120:Arginine / Q000737:chemistry; D001554:Benzene / Q000737:chemistry; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002477:Cells / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000737:chemistry; D019384:Nucleic Acid Synthesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010165:Palladium / Q000737:chemistry*; D055672:Static Electricity; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D018797:Cell Cycle Proteins; D006846:Hydrocarbons, Halogenated; D019384:Nucleic Acid Synthesis Inhibitors; D010165:Palladium; D001120:Arginine; D001554:Benzene