Light-driven carbonyl coupling offers a DNA-compatible route to alcohols

Chemists at the Centre for Research in Biological Chemistry and Molecular Materials (CiQUS), part of the Universidade de Santiago de Compostela, have developed a light-driven reaction that joins carbonyl compounds to other molecules, including those containing double bonds. The reaction is mild enough to be used on molecules attached to DNA, and tests with AstraZeneca showed that the DNA tag remained largely readable. The work, led by Manuel Nappi, is reported in the Journal of the American Chemical Society.

Why DNA-encoded libraries limit the chemistry

Drug discovery depends on testing very large numbers of compounds against a biological target. DNA-encoded libraries (DELs) make this practical by tagging each compound with a short DNA sequence that records its identity. Compounds that bind a target can then be picked out and identified by reading the sequence, rather than by handling each molecule separately.

The approach has a built-in constraint. DNA is chemically fragile, so every reaction used to build the library must work in conditions the tag can tolerate. Harsh reagents, strongly reducing environments and extreme temperatures can damage the DNA or alter its sequence, and a corrupted tag no longer reliably identifies its compound. Each new DNA-compatible reaction therefore widens the chemical space a library can cover.

What the new reaction does

The team's strategy couples carbonyl compounds, such as aldehydes and ketones, with partners that include alkenes. The products are aliphatic alcohols, a structural feature found in many molecules of pharmaceutical interest.

The method uses a catalyst and light to activate the starting materials. In doing so it avoids the strongly reducing conditions that often limit which molecules can take part and that tend to interfere with reactions in the presence of DNA. The reaction runs at room temperature and tolerates a broad range of coupling partners, which suits cases where delicate functional groups must survive. The paper's title, Reductive Couplings Via Nucleophilic Photoactivation of Carbonyls, indicates that light is used to make the carbonyl group react as a nucleophile, although the source summary does not describe the mechanism in detail.

Testing on DNA

The researchers carried out the reaction on DNA-attached substrates and showed that a range of molecular structures could be introduced under conditions compatible with DEL technology. AstraZeneca collaborated on this part of the work and helped judge whether the method suits drug-discovery use.

That collaboration was especially useful for experiments with longer DNA fragments, closer in size to those used in real libraries. With fragments 59 nucleotides long, the DNA was largely preserved and could still be read. Only very low levels of sequence change were detected, which matters because even small error rates can blur the link between a compound and its barcode.

Significance and open questions

The study adds a new way of modifying DNA-linked molecules and increases the toolkit for assembling libraries. Photochemical methods are attractive here because light can trigger reactivity without the harsh reagents that damage DNA.

The available summary does not give yields, the number of substrates tested, or the identity of the catalyst, so the full scope of the method is best judged from the paper itself. The tests described were also reactions on DNA fragments, not the construction and screening of a complete library. Demonstrating performance across the many building blocks and multi-step sequences used in full DEL synthesis, and showing that the resulting compounds yield useful hits in screening, would be the natural next tests of its practical value.

Source: Novel chemical reaction expands options for building DNA-encoded libraries (Phys.org, 31 October 2026).

Image: AI-generated illustration.