Synthesis and Characterization of the Novel Nε-9-Fluorenylmethoxycarbonyl-l-Lysine N-Carboxy Anhydride. Synthesis of Well-Defined Linear and Branched Polypeptides

Abstract

The synthesis of well-defined polypeptides exhibiting complex macromolecular architectures requires the use of monomers that can be orthogonally deprotected, containing primary amines that will be used as the initiator for the Ring Opening Polymerization (ROP) of N-carboxy anhydrides. The synthesis and characterization of the novel monomer Nε-9-Fluorenylmethoxycarbonyl-l-Lysine N-carboxy anhydride (Nε-Fmoc-l-Lysine NCA), as well as the novel linear Poly(Nε-Fmoc-l-Lys)n homopolypeptide and Poly(l-Lysine)78–block–[Poly(l-Lysine)10–graft–Poly(l-Histidine)15] block-graft copolypeptide, are presented. The synthesis of the graft copolypeptide was conducted via ROP of the Nε-Boc-l-Lysine NCA while using n-hexylamine as the initiator, followed by the polymerization of Nε-Fmoc-l-Lysine NCA. The last block was selectively deprotected under basic conditions, and the resulting ε-amines were used as the initiating species for the ROP of Nim-Trityl-l-Histidine NCA. Finally, the Boc- and Trt- groups were deprotected by TFA. High Vacuum Techniques were applied to achieve the conditions that are required for the synthesis of well-defined polypeptides. The molecular characterization indicated that the polypeptides exhibited high degree of molecular and compositional homogeneity. Finally, Dynamic Light Scattering, ζ-potential, and Circular Dichroism measurements were used in order to investigate the ability of the polypeptide to self-assemble in different conditions. This monomer opens avenues for the synthesis of polypeptides with complex macromolecular architectures that can define the aggregation behavior, and, therefore, can lead to the synthesis of “smart” stimuli-responsive nanocarriers for controlled drug delivery applications.

Preparation and characterization of cationic pullulan-based polymers with hydrophilic or amphiphilic characteristics for drug delivery

“…Different polymerization routes are used to obtain PZLL; however, ring-opening polymerization (ROP) of amino acid N-carboxyanhydride (NCA) monomers is the most common synthesis [27,28]. Polypeptides exhibit advantages of natural protein properties, such as secondary and tertiary structures, and α-helical conformation, promoting self-assembly into complex three-dimensional structures [29,30]. In this context, PZLL is a promising candidate for grafting onto the pullulan backbone to obtain a versatile polypeptide-based copolymer [24,30].…”

“…Polypeptides exhibit advantages of natural protein properties, such as secondary and tertiary structures, and α-helical conformation, promoting self-assembly into complex three-dimensional structures [29,30]. In this context, PZLL is a promising candidate for grafting onto the pullulan backbone to obtain a versatile polypeptide-based copolymer [24,30].…”