While performing their essential functions, nucleic acids encounter a variety of disturbances, such as strand cleavage and ligation, local conformational changes, base damage, flipping and chemical modification. Fluorescent nucleosides continue to play a major role in the biophysical study of these processes. This research aims to add a very important but missing capability to the previously studied fluorescent nucleoside analogues: brightness sufficient to enable single-molecule biophysics and tracking labeled nucleic acids by fluorescence microscopy. These advanced features will give a foundation for future applications of fluorescent nucleosides to the investigation of nucleic acid transport, metabolism, regulatory processes and interactions with potential therapeutic agents in living cells, advance new diagnostic approaches and facilitating drug discovery. The specific aim to pursue this goal is to design, synthesize, and characterize a new emissive fluorescent thymidine analogue designed to maximize brightness red-shift the absorption and emission as compared with existing fluorescent nucleoside analogues. We designed a new tricyclic thymidine analogue with conjugated features expected to maximize fluorescence intensity and to lower the HOMO–LUMO gap, thereby red-shifting absorption and emission. The design and synthesis involves C-riboside formation, which is needed for the desired conjugated system. The main challenge of the 3-step synthesis is regioselectivity of an arene bromination needed for the Heck reaction to produce the C-ribosed. Throughout the research, multiple regioselective director catalysts were used at a high temperature, monitoring by TLC, investigating with NMR, and finally obtaining evidence for the formation of the desired isomer as a minor product. Ongoing work is directed at achieving the desired regioselectivity, which will enable us to complete the synthesis and test this new fluorescent nucleoside analogue.

Design and synthesis of new fluorescent thymidine analogues

2019 Spring National Meeting

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