Abstract
We present a trifunctional scaffold designed for the solid-phase synthesis of trimodal compounds. This scaffold holds two alkyne arms in a free and TIPS-protected form for consecutive CuAAC (copper(I)-catalyzed azide–alkyne cycloaddition), one Fmoc-protected hydrazide arm for reaction with aldehydes, and one carboxylic acid arm with CF2 groups for attachment to the resin and 19F-NMR quantification. This scaffold was attached to a resin and derivatized with model azides and aliphatic, electron-rich or electron-poor aromatic aldehydes. We identified several limitations of the scaffold caused by the instability of hydrazones in acidic conditions, in the presence of copper during CuAAC, and when copper accumulated in the resin. We successfully overcame these drawbacks by optimizing synthetic conditions for the derivatization of the scaffold with aromatic aldehydes. Overall, the new trifunctional scaffold combines CuAAC and hydrazone chemistries, offering a broader chemical space for the development of bioactive compounds.
Highlights
Multifunctional scaffolds are precious tools used in chemical biology [1] and polymer science [2].Such scaffolds bear two or more arms, each with orthogonal chemical properties
We developed a new variant of a trifunctional scaffold designed for the solid-phase synthesis of combinatorial libraries
The scaffold 2 can be substituted by two different azides and an aromatic aldehyde, which extends its scope compared to our first trialkyne-based scaffold 1
Summary
Multifunctional scaffolds are precious tools used in chemical biology [1] and polymer science [2]. Such scaffolds bear two or more arms, each with orthogonal chemical properties This allows for the construction of complex multimodal structures by “plugging in” different fragments (e.g., fluorescence tags, polymers, drugs) into the scaffold arms [1], which can be used to mimic discontinuous protein epitopes [3]. With this in mind, we developed a trifunctional scaffold designed for the combinatorial solid-phase syntheses of protein binders [4].
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