Lysine-based dendrimers

B. W. Greatex, S. J. Brodie, R. H. Fumeaux, S. M. Hook, W. T. McBumey, G. F. Painter, T. Rades, and P. M. Rendle, The synthesis and immune stimulating action of mannose-capped lysine-based dendrimers, Tetrahedron, 65 (2009) 2939-2950. 

Rao and Tam[19 reported the connection of a 24-residue peptide to a small, lysine-based dendrimer (Scheme 7.3). The peptide connection was effected via treatment of the octameric, glyoxylyl-terminated dendrimer 15 with the 1,2-aminothiol polypeptide 16 to afford the thiazolidinyl peptide dendrimer 17. The thiazolidine linkage also introduces a new asymmetric center. 

Figure 15 shows both a 2D representation of a lipophilic dendrimer based on lysines, with terminal alkyl groups (84) and a polyamidoamine (PAMAM) dendrimer, now widely used experimentally. The versatility of almost endless variations in internal and external groups makes this a fascinating field of nanotechnology. The unreacted version of lysine-based dendrimer will have terminal amine groups and hence be cationic... 

Figure 15 (A) A hydrophobic poly(lysine)-based dendrimer with 64 alkyl surface groups and a glycine core, as synthesized by T. Sakthivel. (B) a PAMAM dendrimer showing the terminal amine groups. Abbreviation-. PAMAM, polyamidoamine.

Scheme 9 Release of the benzyl diammonium central core template from an L-lysine-based supramolecular dendrimer by the addition of potassium ions, a competitive guest for benzo-[18]-crown-6." ...

PAMAM, Poly-L-Lysine and Pentaerythritol-Based Dendrimers.721... 

Recendy, an amino acid-based dendrimer was PEGylated and conjugated to camptothecin in an effort to provide a new dmg delivery platform. Fox et al. synthesized a second-generation lysine dendron, which was subsequently functionalized with aspartic acid, providing two different functionalities at the periphery an amine and a carboxylic add. The... 

The first synthesized dendrimers were poly(amide amine) (PAMAM) (Tomalia etal., 1985), poly(propyleneimine) (PPI) (Buhleier etal., 1978) andpoly(lysine)-based... 

A poly(L-lysine) dendrimer 23 which carries 16 free-base porphyrins in one hemisphere and 16 Zn porphyrins in the other has been synthesized and studied in dimethylformamide solution [54]. In such a dendrimer, energy transfer from the Zn porphyrins to the free-base units can occur with 43% efficiency. When the 32 free base and zinc porphyrins were placed in a scrambled fashion, the efficiency of energy transfer was estimated to be 83% [55]. Very efficient (98%) energy transfer from Zn to free-base porphyrins was also observed in a rigid, snowflake-shaped structure in which three Zn porphyrin units alternate with three free-base porphyrin units [56]. 

Other supramolecular structures such as dendrimers have also been synthesized with zinc-containing porphyrins. Sixteen free base and sixteen zinc porphyrin units were added at the fifth generation of dendritic poly(L-lysine) and intramolecular fluorescence energy transfer was observed.823 Assembly of supramolecular arrays in the solid state has been achieved with the incorporation of an amide group for hydrogen bonding. Zinc meso-tetra(4-amidophenyl)porphyrin... 

Other types of branched peptide dendrimers, known as multiple antigen peptides (MAPs), have been synthesized to mimic proteins for applications, for instance as synthetic vaccines, serodiagnostics, peptide inhibitors and intracellular delivery vehicles. Since this concept has been recently described in detail elsewhere [11], only the conceptual framework will be briefly presented here. Tam and coworkers have developed a dendritic core based on lysine units for the construction of MAPs [12-15] (Fig. 3). Carrying antigens at their periphery these MAPs have been designed to increase antigenicity and immunogenicity of peptides. 

For the synthesis of perfectly dendronized sohd-phase polymers (Fig. 7.4) various dendritic structures were prepared based on amide connections [6]. For example, the naturally occurring amino acid lysine was used as a building block in creating a dendritic scaffold [33]. The synthesis of symmetrical tri-branching den-drimers on aminomethyl polystyrene macrobeads was also described in literature [34]. Recently, aryl ether dendrimers were prepared on hydroxymethyl polystyrene using a Mitsunobu reaction with 3,5-bis(acetoxymethyl)phenol [35]. 

Figure 14.9 (a) Supramolecular dendrimer based on L-lysine derived dendrons assembled by an... 

Roy and coworkers have designed inhibitors of influenza virus hemagglutinin based on several different dendrimer backbones [109,110]. Using solid phase syntheses, they generated sialic acid-displaying dendrimers based on a poly-L-lysine core structure (O Fig. 17) as ligands for influenza virus hemagglutinin. These dendrimers, which bear 2, 4, 8, or 16 pendant sialic... 

The use of polycationic moieties in drug delivery has been a subject of considerable interest for the past several decades. One of the earliest demonstrations of the potential value of polycations in chug delivery was a study by Tan in 1977, which demonstrated increased uptake of the SV40 virus when infections were carried out in the presence of polycations.1 Other early efforts involved direct cationization of proteins to enhance cellular uptake.2,3 Simultaneously, extensive investigations of the ability of a variety of polycationic vehicles to enhance the uptake of DNA were made.4 These vehicles include cationic liposomes,5 6 poly-L-lysine,7 polyethe-leneimine,8 amino-dendrimers,9 and a variety of other natural and synthetic polycations. Only in recent years, however, has the surprisingly diverse potential of polycation-based delivery systems been realized. This revelation has come primarily from the discovery and utilization of nonclassical transport-based pathways. 

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