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1.
Chemistry ; 29(42): e202300603, 2023 Jul 26.
Article in English | MEDLINE | ID: mdl-37184619

ABSTRACT

DNA-Encoded Libraries (DELs) are becoming widely established as a hit identification strategy for drug discovery campaigns. Their successful application relies on the availability and efficiency of the reactions that can be carried out on DNA. These reactions should proceed with high conversion to the desired product and have a broad substrate scope to synthesise chemically diverse and drug-like DELs. The Sonogashira coupling provides a unique means of coupling an sp-hybridized carbon centre to an aryl halide and methods to achieve this reaction on DNA are highly desirable. We report the application of our micellar technology for on-DNA chemistry to the Sonogashira reaction. This method gives highly efficient conversions for the coupling of (hetero)aromatic and aliphatic alkynes to (hetero)aryl iodides and bromides allowing the preparation of highly diverse DELs.


Subject(s)
DNA Replication , Micelles , Catalysis , DNA , Carbon
2.
Angew Chem Int Ed Engl ; 61(3): e202111927, 2022 01 17.
Article in English | MEDLINE | ID: mdl-34748693

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 have not been amenable to DEL chemistry. We report a catalytic hydrogen transfer reaction using Pd/C, HCONH4 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.


Subject(s)
DNA/chemical synthesis , Hydrogen/chemistry , Carbon/chemistry , Catalysis , DNA/chemistry , Gene Library , Hydrogenation , Nucleic Acid Conformation , Palladium/chemistry , Quaternary Ammonium Compounds/chemistry , Sulfonamides/chemistry , Thiadiazoles/chemistry
3.
Angew Chem Weinheim Bergstr Ger ; 134(3): e202111927, 2022 Jan 17.
Article in English | MEDLINE | ID: mdl-38505343

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 have not been amenable to DEL chemistry. We report a catalytic hydrogen transfer reaction using Pd/C, HCONH4 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.

4.
J Org Chem ; 86(23): 17257-17264, 2021 12 03.
Article in English | MEDLINE | ID: mdl-34788051

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.


Subject(s)
Amines , Micelles , Amination , DNA/genetics , Ligands
5.
Chem Sci ; 12(27): 9475-9484, 2021 Jul 14.
Article in English | MEDLINE | ID: mdl-34349922

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.

6.
Bioorg Med Chem ; 43: 116273, 2021 08 01.
Article in English | MEDLINE | ID: mdl-34147943

ABSTRACT

DNA-encoded libraries (DELs) are becoming an established technology for finding ligands for protein targets. We have abstracted and analysed libraries from the literature to assess the synthesis strategy, selections of reactions and monomers and their propensity to reveal hits. DELs have led to hit compounds across a range of diverse protein classes. The range of reactions and monomers utilised has been relatively limited and the hits are often higher in molecular weight than might be considered ideal. Considerations for future library designs with reference to chemical diversity and lead-like properties are discussed.


Subject(s)
DNA/chemistry , Drug Design , Small Molecule Libraries/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Small Molecule Libraries/chemical synthesis , Structure-Activity Relationship
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