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.
A catalytic hydrogen transfer reaction using Pd/C, HCONH4 and the micelle‐forming surfactant, TPGS‐750‐M for hydrogenolysis of Cbz‐protected amines and benzyl protected alcohols and hydrogenation of alkenes, alkynes, nitros, nitriles, halides and aldehydes of DNA‐conjugated substrates is described. The methodology is fully compatible with DNA‐amplification and sequencing, demonstrating its applicability to DEL synthesis. This method will enable synthetic DEL sequences using orthogonal protecting groups.
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.
A micelle‐mediated Sonogashira reaction between on‐DNA (hetero)aryl iodides or bromides and (hetero)aryl or aliphatic terminal alkynes. The methodology shows broad substrate scope in terms of both coupling partners and we demonstrate that the methodology is fully compatible with library synthesis protocols and DNA encoded and decoding. This methodology will enable the synthesis of alkynyl(hetero)biaryls or it could be used for subsequent derivatization to alternative products, such as the corresponding alkane or heterocycles.
The capability of DNA encoded libraries (DELs) as a method of small molecule hit identification is becoming widely established in drug discovery. While their selection method offers advantages over ...more traditional means, DELs are limited by the chemistry that can be utilized to construct them. Significant advances in DNA compatible chemistry have been made over the past five years; however such procedures are still often burdened by substrate specificity and/or incomplete conversions, reducing the fidelity of the resulting libraries. One such reaction is the Heck coupling, for which current DNA-compatible protocols are somewhat unreliable. Utilizing micellar technology, we have developed a highly efficient DNA-compatible Heck reaction that proceeds on average to 95% conversion to product across a broad variety of structurally significant building blocks and multiple DNA conjugates. This work continues the application of micellar catalysis to the development of widely applicable, effective DNA-compatible reactions for use in DELs.
DNA-encoded libraries (DELs) offer great promise for the discovery of new ligands for proteins. Many current reactions used for DEL synthesis do not proceed efficiently over a wide range of ...substrates. Combining a diverse array of multicomponent reactions with micellar-promoted Suzuki–Miyaura cross-coupling provides a strategy for synthesizing highly diverse DELs with exceptionally high fidelity. These results demonstrate that the micellar Suzuki–Miyaura reaction has exceptional functional group tolerance and broad applicability.
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.
Highly efficient forward and reverse on-DNA amide couplings were developed exploiting hydrophobic linkers in combination with the micelle forming surfactant TPGS-750M. The method is highly effective for a wide range of substrates in the synthesis of DNA-encoded libraries.
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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.
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.
A catalytic hydrogen transfer reaction using Pd/C, HCONH4 and the micelle‐forming surfactant, TPGS‐750‐M for hydrogenolysis of Cbz‐protected amines and benzyl protected alcohols and hydrogenation of alkenes, alkynes, nitros, nitriles, halides and aldehydes of DNA‐conjugated substrates is described. The methodology is fully compatible with DNA‐amplification and sequencing, demonstrating its applicability to DEL synthesis. This method will enable synthetic DEL sequences using orthogonal protecting groups.
We have a medical workforce crisis where we have insufficient trainees, demonstrated by rota gaps, and in turn nearly half of advertised consultant physician posts cannot be appointed to. Most ...physicians retire around age 62, and already 5% of the total consultant workforce is those who have retired and returned. If those reaching retirement age chose not to retire but continue working less than full time this would, at least in part, benefit the workforce and utilise valuable skills and experience to the benefit of the individual, the wider medical community and therefore our patients.
Overall, for physicians seeking national awards, women account for 32% of applicants for bronze awards, 24% for silver awards, and 17% for gold awards. ...fewer women apply (particularly for senior ...awards) than men. An Equality and Inclusion task group reviewed the RCP approaches in a several key areas, including the appraisal systems regarding CEAs.3 Recommendations included making the process more open and the selection procedure and demographics of the scorers available, ensuring there is evidence that the scorers have had diversity training, and introducing a system to ensure fair gender and ethnic representation. In 2017, Mark Porter5 stated “It's about challenging the structures that entrench inequality, but also about challenging our own behaviour and attitudes, and those we experience every day. ...we are truly equal, we are all diminished”.
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