Convergent Assembly and Surface Modification of Multifunctional Dendrimers by Three Consecutive Click Reactions

Abstract

Multifunctional dendrimers bearing two or more surface functionalities have the promise to provide smart drug delivery devices that can for example combine tissue targeting and imaging or be directed more precisely to a specific tissue or cell type. We have developed a concise synthetic methodology for efficient dendrimer assembly and heterobifunctionalization based on three sequential azide-alkyne cycloadditions. The methodology is compatible with biologically important compounds rich in chemical functionalities such as peptides, carbohydrates and fluorescent tags. In the approach, a strain promoted azide-alkyne cycloaddition (SPAAC) between polyester dendrons modified at the focal point with an azido and 4-dibenzocyclooctynol (DIBO) moiety provided dendrimers bearing terminal and TMS-protected alkynes at the periphery. The terminal alkynes were outfitted with azido-modified polyethylene glycol (PEG) chains or galactosyl residues using CuI catalyzed azide-alkyne cycloadditions (CuAAC). Next, a one-pot TMS-deprotection and second click reaction of the resulting terminal alkyne with azido-containing compounds gave multifunctional dendrimers bearing complex biologically active moieties at the periphery.

Branched Polyhedral Oligomeric Silsesquioxane Nanoparticles Prepared via Strain-Promoted 1,3-Dipolar Cycloadditions

“…The azido-modified fluorescein 4 was prepared as described previously. 45 The 2-azidopentyl β - d -galactopyranosyl-(1→4)- β - d -glucopyranoside ( 5 ) and azido-PEG derivatives 6 and 7 were prepared as described previously. 39 Reactions were performed at room temperature (20–22 °C), unless stated otherwise.…”

Multivalent glycoconjugates in medicinal chemistry

“…6, bearing sugars and Arg-Gly-Asp (RGD) peptides at the periphery. 29 A previously reported multivalent dendrimer with dual function, recognition and detection, containing 16 mannose units and 2 coumarin chromophores, exhibited 240-fold greater potency than monomeric mannose in standard hemagglutination assays using Concanavalin A (Con A), with a relative activity of 15 with thiourea-linked galactose or lactose moieties at the upper rim (Fig. 7).…”

“…28 Multifunctional dendrimers bearing two surface functionalities, ''Janus dendrimers'', might be useful as drug delivery devices that can combine tissue targeting and imaging, or be directed to a specific cell type. Boons and co-workers 29 have developed a methodology for the assembly of dendrimers having two different functions, based on three sequential azide-alkyne cycloadditions (Fig. 5).…”

Protected Maleimide Building Blocks for the Decoration of Peptides, Peptoids, and Peptide Nucleic Acids

“…9 One of the options consisted in attaching different alkynes to a scaffold, either combinations of strained and terminal alkynes, 10 or of unprotected and orthogonally protected alkynes. [11][12][13][14] Subsequent Huisgen reactions with azides, with or without Cu(I) or after the required deprotection treatment, allowed new building blocks to be placed where desired.…”