Submonomer Synthesis of Inverse Polyamidoamine (i‐PAMAM) Dendrimer Antibacterials

Abstract

Herein we report that the submonomer method for peptoid synthesis enables access to pure i‐PAMAM dendrimers up to 16 amino termini by a divergent solid‐phase synthesis using the inexpensive bis(3‐trifluoroacetamidopropyl)amine as branching unit. We exemplify this new and efficient approach by a structure‐activity relationship study of antibacterial dendrimers obtained by appending the polycationic i‐PAMAM dendrimer to a hydrophobic core consisting of either an oligoleucine peptide or an oligo‐N‐isobutylglycine peptoid. These non‐hemolytic dendrimers kill Gram‐negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli as well as the Gram‐positive MRSA by a non‐membrane disruptive mechanism involving aggregation of intracellular contents as reported for antimicrobial peptoids.

Access to Diverse Glutamic Acid Dendrons and a Janus Peptide Dendrimer Using an Atypical Solid Phase Synthesis

“…In recent years, peptide dendrons and dendrimers have been extensively used in medical science because of their biocompatibility and resistance to proteolytic degradation when a single amino acid is present between the branching points. 8,9 Also, peptide dendrons have been explored as antimicrobial, 10 antibacterial, 11 antifungal, 12 antiamyloid, 13 and antiviral agents 14 and synthetic vaccines. 15 Since the invention of solid phase peptide synthesis by Bruce Merrifield in 1960s, 16 the solid phase synthetic approach has become the method of choice for its rapid synthesis and straightforward workup procedure, which utilizes a simple filtration protocol of the solid support.…”