Investigating the synthesis of dodeca oligomers of Sarcosine using Fmoc-Sar-OH, Fmoc-(Sar)2-OH and Fmoc-(Sar)4-OH

Introduction

Linkerology®, (1) a technique with increasing impact in the drug discovery arena, is usually based on the use of a linear molecule that binds two moieties of a drug. Examples of these can be found in Antibody-Drug Conjugates (ADCs) for cancer, where the linker connects the cytotoxic drug to the antibody, (2) or in the most recent drugs approved for diabetes type 2 or obesity, where the linker connects the peptide drug with the fatty acid responsible for its binding to albumin to extend the in vivo half-life of the drug (3).

In terms of linkers, those most widely used are based on poly- or oligomers of ethylene glycol. Polyethylene glycol (PEG) has been widely employed in drug discovery because it enhances the circulation of half-life medication (4).
Due to the excellent properties of PEG, among which are solubility in water, low cellular toxicity and protein resistance. PEGylated products have been used for the treatment of a variety of conditions, including melanoma, hepatitis, hematological cancer, and autoimmune diseases (5), to reduce the limitations of peptide-based drugs (6).
Unfortunately, clinical applications of PEGylated therapeutic molecules are hindered mainly because of their non-biodegradable properties, which may also result in cumulative toxic effects upon repetitive administration. Thus, Peginesatide—a peptide drug with a high PEG-content—initially approved by the FDA in 2012 was withdrawn one year later due to several adverse effects (7). Another potential issue associated with the use of PEGs in drug discovery is the challenge of synthesizing monodisperse PEGs/OEGs, as well as their high cost, which often poses an obstacle to mass use. Furthermore, recent studies have shown evidence that pegylated products exhibit immunogenicity, which reduces their efficiency as therapeutic agents (8, 9). Therefore, there is a growing need for alternative linkers for polymer-based conjugation, including, but not limited to, poly(2-oxazolines) (10), polyglycerol (11), zwitterionic polymers (12), OEGylated poly(meth)acrylates (13) and poly(amino acids)/oligomer peptides (14).