Expanding the scope of DNA encoded library chemistry using micelles.

DNA-encoded chemical libraries (DELs) are becoming established as an important capability in modern hit finding across the pharmaceutical industry. Indeed, a DEL is a strategy used to identify a hit molecule during screening campaigns that can lead to potential drug candidates. Synthesis of DELs relies on carrying out multiple transformations on DNA conjugated substrates. The conditions employed for each step must, therefore, be compatible with the DNA tag. In other words, reactions have to be carried out in aqueous conditions at high dilution and be successful across a wide range of substrates.

The use of micellar reaction conditions is increasingly becoming established as a means of promoting challenging transformations in water. In particular, modern micelle-forming surfactants such as TPGS and Nok promote a range of metal catalysed transformations, such as Suzuki couplings, Buchwald- Hartwig aminations and olefin metathesis and can be employed in a facile manner with low cost. The efficiency of micellar transformations arises from the localisation of organic reagents and substrates within the cages formed within the micelles resulting in exceptionally high local concentrations of reacting species within so-called "nanoreactors". We believe that this methodology could be of great utility in carrying out DEL synthesis as micelles could form around the organic substrate portion of the substrate, localising the reactive species to the site of reaction and protecting the DNA tag, which would remain in the external aqueous environment.

This project will thus expand the range of chemistry available for generating DELs using micellar "nanoreactors", which will increase the efficiency of diversity generating reactions and protect the DNA from degradation. The concept is based on increasing evidence that micellar conditions enhance the efficiency of DEL synthesis, building on our first results with Suzuki-Miyaura cross couplings. Work conducted within the group has revealed that use of TPGS-750-M surfactant for couplings on DNA led to clean conversions to the desired biaryl products with unprecedented efficiency (>98% on average) with no detectable DNA damage. We will expand on these results to extend the range of transformations that can be applied to micellar conditions, focusing on processes that are unsuccessful under traditional DEL conditions.

Initially, we will focus on the application of micellar transformations to Nucleophilic Aromatic Substitution reactions (SNAr). SNAr procedure is used extensively in library synthesis frequently for the addition of amines to heterocyclic electrophiles to produce products with desirable properties. SNAr is reported to be the third most cited reaction both in medicinal chemistry research and scale-up processes. This project will therefore have a significant impact in order to produce reliable libraries to identify lead-like molecules. Despite being employed in DEL synthesis, SNAr use has been largely restricted to highly activated electrophiles such as halotriazines and pyrimidines bearing an electron withdrawing group. Less activated electrophiles are not sufficiently reactive to combine efficiently with the broad range of nucleophiles to produce large libraries under DEL conditions. It has recently been shown that micellar conditions significantly promote a range of general SNAr reactions at reduced temperatures off-DNA. The methodology developed on-DNA will be applied to generate libraries for screening and potentially identify lead-like molecules.

Theme: Healthcare Technologies