Development and design of the tertiary amino effect reaction for DNA-encoded library synthesis

Xia, Tian; Basarab, Gregory S.; Selmi, Nidhal; Kogej, Thierry; Zhang, Ying; Goodnow, Robert A.

doi:10.1039/c6md00088f

Cited by 26 publications

(11 citation statements)

References 38 publications

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“…The chemical reactions described for DEL synthesis must be robust, high yielding, cover broad reactant scope, and must preserve the integrity of the DNA code . More than 40 reaction classes have been described “on-DNA” with moderate to high success rates, , and more synthetic transformations are being recently reported expanding the “on-DNA”-compatible chemistry tool-box. − …”

mentioning

confidence: 99%

Mild and Efficient Palladium-Mediated C–N Cross-Coupling Reaction between DNA-Conjugated Aryl Bromides and Aromatic Amines

Beato¹,

Priego²,

Gironda-Martínez³

et al. 2019

ACS Comb. Sci.

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DNA-encoded library technology (ELT) has emerged in the pharmaceutical industry as a powerful tool for hit and lead generation. Over the last 10 years, a number of DNA-compatible chemical reactions have been published and used to synthesize libraries. Among the most commonly used reactions in medicinal chemistry is the C−N bond formation, and its application to DNA-encoded library technology affords an alternative approach to identify high-affinity binders for biologically relevant protein targets. Herein we report a newly developed Pd-promoted C−N cross coupling reaction between DNA-conjugated aryl bromides and a wide scope of arylamines in good to excellent yields. The mild reaction conditions should facilitate the synthesis of novel DNA-encoded combinatorial libraries.

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mentioning

confidence: 99%

Mild and Efficient Palladium-Mediated C–N Cross-Coupling Reaction between DNA-Conjugated Aryl Bromides and Aromatic Amines

Beato¹,

Priego²,

Gironda-Martínez³

et al. 2019

ACS Comb. Sci.

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“…Confirmation of the structure of an on‐DNA reaction product is often complicated by the fact that LC/MS is the only readily applicable technique for analyzing on‐DNA compounds. For special cases, NMR analysis of 13 C‐labeled on‐DNA substrates was used to confirm product formation . Our group has used indirect approaches to measure the stereochemistry of on‐DNA reactions by using HPLC.…”

Section: Resultsmentioning

confidence: 99%

Zirconium(IV)‐Catalyzed Ring Opening of on‐DNA Epoxides in Water

Fan

Davie

2017

ChemBioChem

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DNA-encoded library technology (ELT) has spurred wide interest in the pharmaceutical industry as a powerful tool for hit and lead generation. In recent years a number of "DNA-compatible" chemical modifications have been published and used to synthesize vastly diverse screening libraries. Herein we report a newly developed, zirconium tetrakis(dodecyl sulfate) [Zr(DS) ] catalyzed ring-opening of on-DNA epoxides in water with amines, including anilines. Subsequent cyclization of the resulting on-DNA β-amino alcohols leads to a variety of biologically interesting, nonaromatic heterocycles. Under these conditions, a library of 137 million on-DNA β-amino alcohols and their cyclization products was assembled.

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“…This is in agreement with a previous report employing a variant of the Knoevenagel condensation in solution-phase DNA-encoded library synthesis. 39 This opened the door to incorporating cyanoacrylamides into a DNA-encoded OBOC library. The library was prepared on 10 μm TentaGel resin along with several thousand 160 μm beads that served as "sentinels" because they contain sufficient material for postsynthesis analysis of both the DNA and synthetic ligands.…”

Section: Acs Combinatorial Sciencementioning

confidence: 99%

DNA-Compatible Solid-Phase Combinatorial Synthesis of β-Cyanoacrylamides and Related Electrophiles

Pels

Dickson

et al. 2018

ACS Comb. Sci.

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We demonstrate that the Knoevenagel condensation can be exploited in combinatorial synthesis on the solid phase. Condensation products from such reactions were structurally characterized, and their Michael reactivity with thiol and phosphine nucleophiles is described. Cyanoacrylamides were previously reported to react reversibly with thiols, and notably, we show that dilution into low pH buffer can trap covalent adducts, which are isolable via chromatography. Finally, we synthesized both traditional and DNA-encoded one-bead, one-compound libraries containing cyanoacrylamides as a source of cysteine-reactive reversibly covalent protein ligands.

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Development and design of the tertiary amino effect reaction for DNA-encoded library synthesis

Abstract: The tertiary amino effect reaction was explored and developed for application to DNA-encoded library synthesis.

Cited by 26 publications

References 38 publications

Mild and Efficient Palladium-Mediated C–N Cross-Coupling Reaction between DNA-Conjugated Aryl Bromides and Aromatic Amines

Mild and Efficient Palladium-Mediated C–N Cross-Coupling Reaction between DNA-Conjugated Aryl Bromides and Aromatic Amines

Zirconium(IV)‐Catalyzed Ring Opening of on‐DNA Epoxides in Water

DNA-Compatible Solid-Phase Combinatorial Synthesis of β-Cyanoacrylamides and Related Electrophiles

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