Radiation in the near-infrared region is invisible, but can deeply penetrate living tissue without damaging it. Dye molecules that produce near-infrared light consequently have valuable applications in medical diagnostics, and A*STAR researchers have developed a synthetic approach that can quickly identify ways to fine-tune their emission properties.
One dye known as dihydroxanthene (DHX), although discovered nearly 20 years ago, has attracted a flurry of renewed interest after chemists discovered that small tweaks to a central 'scaffold'—an interlinked framework of three aromatic rings—could switch on bright, near-infrared fluorescence. Current synthetic methods, however, are ill-equipped to access a variety of analogs from a single DHX scaffold. This makes it difficult to comprehend how certain structures can maximize fluorescence.
Jean-Alexandre Richard from A*STAR's Institute of Chemical and Engineering Sciences and co-workers aimed to explore DHX's potential by taking a lead from medicinal chemists, who often generate libraries of potential drug candidates by reacting a common intermediate with a set of reagents. This technique, also known as divergent synthesis, significantly simplifies efforts to screen compounds with desirable properties.
"I saw potential for developing new chemistry to make these dyes because the reported routes were not flexible enough," says Richard. "Our approach gives access to a number of molecules which would have been too time-consuming to obtain through purely de novo synthesis."
To build their library of dyes, the team devised a divergent synthesis where two 'chemical handles' were attached to either end of the DHX scaffold. By giving the handles opposing electron-donating and -accepting capabilities, the team envisioned they could create conditions for a wide range of fluorescence levels. They identified that, by using aldehyde and aryl bromide handles, they could produce the initial scaffold in just one step and on a gram scale.
The researchers first systematically replaced the bromine handle with more than 20 amino-based donors, each with slightly different linear, cyclic, and aromatic structures. Then, they directly swapped the aldehyde handle with a charged aromatic ring group to boost DHX's electron-pulling properties. Optical tests of the dye library enabled the team to rank the analogs in terms of their fluorescence intensity—data that may prove critical for tracking different components in complex biosystems.
The team is excited about the dye's new potential. "The DHX dyes will complement the rather small number of near-infrared dyes now available, and encourage people to consider them a viable option for microscopy, diagnostics and imaging," says Richard.
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Michelle Jui Hsien Ong et al. Divergent Synthesis of Dihydroxanthene-Hemicyanine Fused Near-Infrared Fluorophores through the Late-Stage Amination of a Bifunctional Precursor, Organic Letters (2016). DOI: 10.1021/acs.orglett.6b02564