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Design, synthesis and application of polyphenylene dendrimers for biological / pharmaceutical assays

Authors
Publisher
Johannes Gutenberg-Universität
Publication Date
Disciplines
  • Design

Abstract

Summary Several synthetic strategies affording water soluble polyphenylene dendrimers (PPD) were developed. Single amino acids were introduced on the periphery of the dendrimers using amino acid substituted cyclopentadienones in the last Diels-Alder addition reaction. Alternatively, peptide sequences were attached via a chemoselective reaction, which involved tne addition of the sulfhydryl group of a cysteine residue of an oligopeptide to a maleimide moiety present on the surface of the dendrimer. Further, several desymmetrized PPDs were obtained, each combining the properties of different functional groups. For example a polyphenylene scaffold possessing both cholesterol and pentalysine moieties was synthesized. This water soluble dendrimer was proven to cross the blood brain barrier by in vitro experiment. A new efficient synthetic approach for the desymmetrization of PPDs was also developed. Tetrakis(4-ethynylphenyl)methane was reacted with substoichiometric quantities of tetraphenylcyclopentadienones bearing one polar functional group in a Diels-Alder cycloaddition.. A single ethynyl group was thereby converted to a structurally rigid, selectively functionalized polyphenylene moiety, which serves as a focal point for further transformations or interfacial anchoring. This is the key feature for the design of desymmetrized monodisperse macromolecules with a spherical shape. The remaining unreacted ethynyl groups provide a trifold core for the stepwise elaboration of first- and second-generation polyphenylene dendrons, Lysine decorated PPD were proven non-toxic in vivo and were further used for DNA/RNA complexation and delivery. PPD-siRNA complexes were successfully applied in a gene suppression. In the case of DNA transefection, it was found that synergetic action of the dendrimer polyethylene imine (PEI) leads to 10 fold increase of the gene expression capacity at N/P ratio of 4. The shape persistence of the PPDs ensures the localization of the charges coming from the polypeptide residues on the surface of the molecule. This fact was used for building of a switchable ( pH-controlled) supramolecular gate, composed of alternating layers of lysine and carboxy decorated PPDs. These structures were shown to contain internal nanosized voids whose size can be changed / controlled by a simple change of the pH. The synthetic routes and experiments reported in the present work open the way of the development of new generation RNA/DNA complexing agents and drug carries, particularly interesting for drugs acting in the central nervous system.

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