Isaline F.S.F. Castan

Bio: Isaline F.S.F. Castan is an academic researcher from Newcastle University. The author has contributed to research in topics: Nucleophilic substitution & Chemistry. The author has an hindex of 2, co-authored 2 publications receiving 6 citations.

Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries.

Abstract: DNA encoded libraries (DELs) represent powerful new technology for finding small molecule ligands for proteins and are increasingly being applied to hit finding in medicinal chemistry. Crucial to the synthesis of high quality DELs is the identification of chemical reactions for their assembly that proceed with very high conversion across a range of different substrates, under conditions compatible with DNA-tagged substrates. Many current chemistries used in DEL synthesis do not meet this requirement, resulting in libraries of low fidelity. Amide couplings are the most commonly used reaction in synthesis of screening libraries and also in DELs. The ability to carry out highly efficient, widely applicable amide couplings in DEL synthesis would therefore be highly desirable. We report a method for amide coupling using micelle forming surfactants, promoted by a modified linker, that is broadly applicable across a wide range of substrates. Most significantly, this works exceptionally well for coupling of DNA-conjugated carboxylic acids (N-to-C) with amines in solution, a procedure that is currently very inefficient. The optimisation of separate procedures for coupling of DNA-conjugated acids and amines by reagent screening and statistically driven optimisation is described. The generality of the method is illustrated by the application to a wide range of examples with unprecedented levels of conversion. The utility of the (N-to-C) coupling of DNA-conjugated acids in DEL synthesis is illustrated by the three cycle synthesis of a fully DNA-encoded compound by two cycles of coupling of an aminoester, with intermediate ester hydrolysis, followed by capping with an amine. This methodology will be of great utility in the synthesis of high fidelity DELs.

In-solution direct oxidative coupling for the integration of sulfur/selenium into DNA-encoded chemical libraries

Abstract: Sulfur/selenium-containing electron-rich arenes (ERAs) exist in a wide range of both approved and investigational drugs with diverse pharmacological activities. These unique chemical structures and bioactive properties, if combined with the emerging DNA-encoded chemical library (DEL) technique, would facilitate drug and chemical probe discovery. However, it remains challenging, as there is no general DNA-compatible synthetic methodology available for the formation of C–S and C–Se bonds in aqueous solution. Herein, an in-solution direct oxidative coupling procedure that could efficiently integrate sulfur/selenium into the ERA under mild conditions is presented. This method features simple DNA-conjugated electron-rich arenes with a broad substrate scope and a transition-metal free process. Furthermore, this synthetic methodology, examined by a scale-up reaction test and late-stage precise modification in a mock peptide-like DEL synthesis, will enable its utility for the synthesis of sulfur/selenium-containing DNA-encoded libraries and the discovery of bioactive agents.

On-DNA Transfer Hydrogenolysis and Hydrogenation for the Synthesis of DNA-Encoded Chemical Libraries.

Abstract: DNA-encoded libraries (DELs) are an increasingly popular approach to finding small molecule ligands for proteins. Many DEL synthesis protocols hinge on sequential additions of monomers using split-pool combinatorial methods. Therefore, compatible protecting group strategies that allow the unmasking of reactive functionality (e.g. amines and alcohols) prior to monomer coupling, or the removal of less desirable functionality (e.g. alkenes and alkynes) are highly desirable. Hydrogenation / hydrogenolysis procedures would achieve these ends but has not been amenable to DEL chemistry. We report a catalytic hydrogen transfer reaction using Pd / C, HCONH 4 and the micelle-forming surfactant, TPGS-750-M, which gives highly efficient conversions for hydrogenolysis of Cbz-protected amines and benzyl protected alcohols and hydrogenation of nitros, halides, nitriles, aldehydes, alkenes and alkynes. Application to multicycle synthesis of an encoded compound was fully compatible with DNA-amplification and sequencing, demonstrating its applicability to DEL synthesis. This method will enable synthetic DEL sequences using orthogonal protecting groups.

Micellar Buchwald-Hartwig coupling of aryl and heteroarylamines for the synthesis of DNA-encoded libraries

Abstract: DNA-encoded libraries are a very efficient means of identifying ligands for protein targets in high throughput. To fully maximize their use, it is essential to be able to carry out efficient reactions on DNA-conjugated substrates. Arylamines are privileged motifs in druglike molecules, and methods for their incorporation into DNA-encoded libraries are highly desirable. One of the preferred methods for their preparation, the Buchwald-Hartwig coupling, does not perform well on DNA conjugates using current approaches. We report the application of our recently developed micellar technology for on-DNA chemistry to the Buchwald-Hartwig reaction. Optimization of conditions led to a robust, high-yielding method for the synthesis of DNA-conjugated aryl and heteroarylamines, which is broad in substrate scope for both the arylamine and the DNA-conjugated aryl halide and is fully compatible with DNA-encoding and decoding procedures. This method will enable the preparation of diverse, high-fidelity libraries of biarylamines.