Customizable and Regioselective One-Pot N-H Functionalization of DNA Nucleobases to Create a Library of Nucleobase Derivatives for Biomedical Applications

DNA is one of the most exciting biomolecules in nature for developing supramolecular biofunctional nanoarchitectures owing to the highly specific and selective interactions between complementary Watson-Crick base pairing. Herein, simple and one-pot synthetic procedures have been implemented for producing a library of DNA nucleobase derivatives endowed with reactive functional groups for bioconjugation and cross-linking strategies with other (bio)molecules. Purine and pyrimidine molecules have been regioselectively N-H functionalized either via N-alkylation, N-allylation, N-propargylation or Michael-type reactions and structurally characterized. The influence of the reaction conditions was assessed and discussed. The in vitro biocompatibility of the native and nucleobase derivatives was evaluated by culturing them with human fibroblasts, revealing their cytocompatibility. The library of nucleobase derivatives holds great promise for being coupled to different biomolecules, including biopolymeric materials, lipids, and peptides, thus potentially leading to modular supramolecular nanobiomaterials for biomedicine.

Automated summary

DNA nucleobase derivatives with reactive functional groups were synthesized for bioconjugation and cross-linking strategies, showing in vitro biocompatibility with human fibroblasts. This library of derivatives holds great promise for the development of supramolecular nanobiomaterials for biomedicine by coupling with different biomolecules.