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

Hunter, James H.; Anderson, Matthew; Castan, Isaline F.S.F.; Graham, Jessica S.; Salvini, Catherine L.A.; Stanway-Gordon, Harriet A.; Crawford, James J.; Madin, Andrew; Pairaudeau, Garry; Waring, Michael J.

doi:10.1039/d1sc03007h

Cited by 26 publications

(26 citation statements)

References 36 publications

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“…Alternatively, as Cycle 1 inputs, a carboxyl linker can react with amino substrates such as esters of amino acids. However, due to its poorly known instability during specific chemical conversions, as observed in our and others' work, [26] this form of reverse amide linkage has been infrequently employed for DEL synthesis. The limitations of available linkers for DEL synthesis prompted us to create alternatives.…”

Section: Introductionmentioning

confidence: 80%

N‐Alkyl Linkers for DNA‐Encoded Chemical Libraries

Sun

Yang

Xue

et al. 2022

Chemistry An Asian Journal

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A series of novel N‐alkyl linkers that connect small‐molecule library members with their encoding DNA oligonucleotides has been developed. In comparison with the standard amide linker (usually constructed with oligo‐AOP‐NH2), the N‐alkyl linker is not only more chemically stable, but also provides better structural diversity at the linkage point. Chemical variety in the vicinity of the polyglycol terminus, in particular, could affect binding interactions with the target protein. It could have been neglected in previous DNA‐encoded chemical library (DEL) synthesis and screening studies due to the limited linkage alternatives. With these linkers, one can produce versatile key intermediates as Cycle 1 products directly amenable to Cycle 2 chemistry without the use of protecting groups. As a result, a DEL synthesis process that uses the fewest chemical conversions, such as 3‐step, 3‐cycle DELs, can achieve higher synthetic efficiency while creating less DNA tag degradation, resulting in higher quality DELs.

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Section: Introductionmentioning

confidence: 80%

N‐Alkyl Linkers for DNA‐Encoded Chemical Libraries

Sun

Yang

Xue

et al. 2022

Chemistry An Asian Journal

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“… a Reported reaction conversions from ref . b Reported reaction conversions from ref . c Reported reaction conversions from ref . …”

Section: Resultsmentioning

confidence: 99%

“…One solution to the challenge of performing reactions in aqueous media is to use micellar surfactants . We have reported the use of the surfactant TPGS-750-M to promote on-DNA Suzuki–Miyaura and amide coupling reactions . Both reactions proceed with the excellent conversion to the desired products with minimal side reactions.…”

Section: Introductionmentioning

confidence: 98%

Micellar Buchwald–Hartwig Coupling of Aryl and Heteroarylamines for the Synthesis of DNA-Encoded Libraries

2021

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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.

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“…[30] Waring et al investigated both C-to-N and N-to-C amidations under micellar conditions. [31] Initial investigations showed that the structure of the linker between the oligonucleotide and organic handles greatly affects the outcome. While the reaction with the commonly employed PEG-4 linker performed poorly, a more hydrophobic hexadecanoic acid linker provided promising results in the N-to-C coupling (Scheme 8).…”

Section: Amide Bond Formationmentioning

confidence: 99%

“…Waring et al. investigated both C ‐to‐ N and N ‐to‐ C amidations under micellar conditions [31] . Initial investigations showed that the structure of the linker between the oligonucleotide and organic handles greatly affects the outcome.…”

Section: Micellar Synthesis Of Dna‐tagged Moleculesmentioning

confidence: 99%

The Potential of Micellar Media in the Synthesis of DNA‐Encoded Libraries

Novàk

Adamik

Buchholcz

et al. 2022

Chemistry A European J

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DNA-encoded library (DEL) technology has become widely used in drug discovery research. The construction of DELs requires robust organic transformations that proceed in aqueous media under mild conditions. Unfortunately, the application of water as reaction medium for organic synthesis is not evident due to the generally limited solubility of organic reagents. However, the use of surfactants can offer a solution to this issue. Oil-in-water microemulsions formed by surfactant micelles are able to localize hydrophobic reagents inside them, resulting in high local concentrations of the organic substances in an otherwise poorly solvated environment. This review provides a conceptual and critical summary of micellar synthesis possibilities that are well suited to DEL synthesis. Existing examples of micellar DEL approaches, together with a selection of micellar organic transformations fundamentally suitable for DEL are discussed.

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

Abstract: 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.

Cited by 26 publications

References 36 publications

N‐Alkyl Linkers for DNA‐Encoded Chemical Libraries

N‐Alkyl Linkers for DNA‐Encoded Chemical Libraries

Micellar Buchwald–Hartwig Coupling of Aryl and Heteroarylamines for the Synthesis of DNA-Encoded Libraries

The Potential of Micellar Media in the Synthesis of DNA‐Encoded Libraries

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