Modular Assembly Using Sequential Palladium Coupling Gives Easy Access to the SMoC Class of Cellular Transporters
✍ Scribed by Anne-Sophie Rebstock; Cristina Visintin; Elisabetta Leo; Cristina Garcia Posada; Sarah R. Kingsbury; Gareth H. Williams; Kai Stoeber; David L. Selwood
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 776 KB
- Volume
- 9
- Category
- Article
- ISSN
- 1439-4227
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✦ Synopsis
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.