Synthesis of DNA tagged Amides

Unmet Need

Synthesis of DNA encoded libraries is a challenging process because the DNA tags mean that the molecules are only soluble in water, not in organic solvents that are needed for most organic synthesis. Additionally, many organic transformations are incompatible with DNA leading to incomplete reaction and degradation of the DNA tag. Current conditions for carrying out on-DNA amide chemistry use standard aqueous conditions. These conditions can lead to incomplete reaction, decomposition of DNA and low substrate scope. There are limited options for screening conditions to address this as the methods are restricted to water soluble reagents. This means that libraries synthesised using this protocol will be suboptimal – not containing all the intended products and in some cases containing DNA tags that code for the wrong molecule, meaning they are far from ideal for drug screening.

The Technology

The technology is a method for carrying out on-DNA amide chemistry. The technology uses micelles to localise the coupling partners in an organic solvent environment whilst maintaining the DNA tag outside the micelle in an aqueous environment. The DNA tag and the coupling partner are linked via a carbon chain

Applications

• synthesis DNA encoded Libraries for screening for new drug lead molecules
• synthesis of oligonucleotide conjugates

Advantages

The technology leads to full reaction conversion (≥95%) with the DNA tag unaltered on amide compounds.

The technology gives syntheses of DEL amide libraries of much greater fidelity, which will give more robust screening results as well as containing more of the intended compounds. Moreover, the approach should be generally applicable - it potentially enables the application of a much wider range of chemistry, meaning far more diverse libraries can be synthesised (currently, a major limitation of standard methods).

Contact

Tim Blackburn: Tim.Blackburn@newcastle.ac.uk