Abstract
A range of chemistries were explored for the efficient covalent conjugation of DNA to poly(N-isopropylacrylamide) (poly(NIPAM)) in organic solvents. Amide coupling and thiol–ene Michael addition were found to be ineffective for the synthesis of the desired products. However, the inverse electron-demand Diels–Alder (DAinv) reaction between tetrazine (Tz) and norbornene (Nb) was found to give DNA–polymer conjugates in good yields (up to 40%) in organic solvents (N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone), and without the need for a catalyst. Methods for the synthesis of Tz-and Nb- functionalised DNA were developed, along with a post-polymerisation functionalisation strategy for the production of Tz-functionalised polymers.
Highlights
All of this work demonstrates the potential of DNA-polymer conjugates to provide access to highly functional materials
We previously reported that correct catalyst selection could make the copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction a highly efficient chemistry for DNA–polymer conjugation in organic solvents[17]
Since the thiocarbonyl thio groups present in Reversible Addition-Fragmentation Chain Transfer (RAFT) chain transfer agents (CTAs) degrade in the presence of amines, it has always been difficult to incorporate this group into polymers synthesised using the RAFT technique[38]
Summary
All of this work demonstrates the potential of DNA-polymer conjugates to provide access to highly functional materials. The use of amide coupling chemistry, the thiol–ene reaction and the inverse electron demand Diels–Alder (DAinv) reaction were surveyed as potential routes to DNA–polymer conjugates. All of these chemistries have previously been used successfully for macromolecular coupling in solution in the absence of a solid support. Hansell et al used the DAinv reaction between tetrazine (Tz) and norbornene (Nb) to couple polymers synthesised via different routes with high efficiency under ambient conditions[35] While these examples illustrate that these chemistries hold promise, to our knowledge no systematic study exists of their applicability to the synthesis of DNA–polymer conjugates. Poly(NIPAM) was chosen as a model polymer as it is organic- and water-soluble and exhibits temperature-responsive behaviour, a potentially useful characteristic for nanotechnology applications[37]
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