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Modular Assembly Using Sequential Palladium Coupling Gives Easy Access to the SMoC Class of Cellular Transporters
Author(s) -
Rebstock AnneSophie,
Visintin Cristina,
Leo Elisabetta,
Garcia Posada Cristina,
Kingsbury Sarah R.,
Williams Gareth H.,
Stoeber Kai,
Selwood David L.
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200800153
Subject(s) - dna , chemistry , small molecule , biomolecule , transcription factor , in vitro , biophysics , computational biology , combinatorial chemistry , microbiology and biotechnology , biochemistry , biology , gene
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.