Abstract
Addressing intracellular targets is a challenging task that requires potent molecular transporters capable to deliver various cargos. Herein, we report the synthesis of hydrophobic macrocycles composed of both amino acids and peptoid monomers. The cyclic tetramers and hexamers were assembled in a modular approach using solid as well as solution phase techniques. To monitor their intracellular localization, the macrocycles were attached to the fluorophore Rhodamine B. Most molecular transporters were efficiently internalized by HeLa cells and revealed a specific accumulation in mitochondria without the need for cationic charges. The data will serve as a starting point for the design of further cyclic peptoid-peptide hybrids presenting a new class of highly efficient, versatile molecular transporters.
Highlights
Biological membranes envelop intracellular structures, protect them from harmful substances and enable diverse physiological processes
For the design of molecular transporters, the substitution step was performed with four different amines that led to the assembly of the alkylated glycine monomers N1ph (2), N1phpCl (12), N3m (13), and N4am (14, Figure 2)
Thereby, all lipophilic monomers should allow for an accumulation in mitochondria. (Kölmel et al, 2012; Nam et al, 2018) The peptoid monomer N4am (14) served as conjugation site for the fluorophore Rhodamine B
Summary
Biological membranes envelop intracellular structures, protect them from harmful substances and enable diverse physiological processes. Peptide-Peptoid Chimera as Molecular Transporters of certain peptidomimetics could enhance both cellular uptake efficiency and metabolic stability. (Wender et al, 2000; Peretto et al, 2003; Madani et al, 2011; Koren and Torchilin, 2012; Guidotti et al, 2017) Shin et al (Shin et al, 2018) showed that the efficiency of this cellular uptake is significantly increased after cyclization of linear CPPos. As a defined three-dimensional structure caused by cyclization has proved to be beneficial for cellular uptake, (LättigTünnemann et al, 2011; Nischan et al, 2015; Shin et al, 2018; Dougherty et al, 2019; Park et al, 2019), we report the synthesis of macrocyclic tetramers and hexamers as novel molecular transporters.
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