Isocyanide Multicomponent Reactions on Solid-Phase-Coupled DNA Oligonucleotides for Encoded Library Synthesis

Kunig, Verena B. K.; Ehrt, Christiane; Dömling, Alexander; Brunschweiger, Andreas

doi:10.1021/acs.orglett.9b02448

Cited by 64 publications

(53 citation statements)

References 53 publications

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“…Heteroaromatic anilines had to be excluded from the Povarov reaction and substituted b-ketoesters and ureas for the Biginelli reaction are only scarcely available. In agreement with an earlier library analysis, 25 we observed that application of different synthesis methods (here Diels-Alder, Povarov and Biginelli reactions) led to only partially overlapping chemical space from common DNA-coupled starting materials.…”

Section: Cheminformatics Analysis Of Simulated Encoded Heterocycle LIsupporting

confidence: 91%

“…† Our chemically very stable adapter oligonucleotide hexT 7 and three different decamer DNA oligonucleotides (TC 8, ATC 9, and ATGC 10) were incubated with three aqueous acids, as well as 33 metal salts and 20 organocatalysts dissolved in dry organic solvents. To reect plausible reaction conditions, 24,25 the catalysts were incubated with DNA strands at a 200-fold reagent excess for 22 hours at ambient temperature. Aer washing steps and standard DNA cleavage from solid support we quantitated and characterized DNA damage by RP-HPLC and MALDI-TOF mass spectrometric analysis.…”

Section: Resultsmentioning

confidence: 99%

“…[20][21][22][23] We recently reported that CPGcoupled DNA barcodes tolerated Ag(I)-mediated (2 + 3) azomethine ylide cycloadditions, the Yb(III)-mediated Castagnoli-Cushman reaction, 24 and isocyanide multicomponent reactions. 25 Harsher reaction conditions such as the triuoroacetic acid-mediated Pictet-Spengler reaction and Au(I)-mediated pyrazole synthesis were compatible with a chemically very stable, CPG-coupled hexathymidine adapter "hexT". 26 These reports prompted us to compare the stability of solid phasecoupled hexT, pyrimidine DNA and DNA barcodes to a larger number of reagents.…”

Section: Introductionmentioning

confidence: 97%

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Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

et al. 2019

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Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Initiating encoded compound synthesis with solid phase -coupled DNA barcodes does benefi t from choice of organic solvents. Screening of more than 50 metal salts and organic reagents for DNA compatibility suggested reactions for encoded compound synthesis. A ZnCl2-mediated aza-Diels-Alder reaction with Danishefsky's diene and diphenyl phosphate-promoted tetrahydroquinoline and pyrimidinone syntheses by Povarov and Biginelli reactions, respectively, showed a broad substrate scope and were well tolerated by a DNA oligonucleotide.DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Generally, these libraries are synthesized by solution phase combinatorial chemistry requiring aqueous solvent mixtures and reactions that are orthogonal to DNA reactivity. Initiating library synthesis with readily available controlled pore glass-coupled DNA barcodes benefits from enhanced DNA stability due to nucleobase protection and choice of dry organic solvents for encoded compound synthesis. We screened the compatibility of solid-phase coupled DNA sequences with 53 metal salts and organic reagents. This screening experiment suggests design of encoded library synthesis. Here, we show the reaction optimization and scope of three sp 3 -bond containing heterocyclic scaffolds synthesized on controlled pore glass-connected DNA sequences. A ZnCl 2 -promoted aza-Diels-Alder reaction with Danishefsky's diene furnished diverse substituted DNA-tagged pyridones, and a phosphoric acid organocatalyst allowed for synthesis of tetrahydroquinolines by the Povarov reaction and pyrimidinones by the Biginelli reaction, respectively. These three reactions caused low levels of DNA depurination and cover broad and only partially overlapping chemical space though using one set of DNA-coupled starting materials. † Electronic supplementary information (ESI) available: Synthesis and additional tables for screening experiments, reaction optimization experiments and reaction scope. Copies of HPLC traces and MALDI-MS spectra are shown for all discussed DNA conjugates. See a For each: 20 nmol DNA, 200 equiv. (transition) metal salt or organocatalyst A-H, 50 mL dry solvent, r.t., 22 h. b 50 mL of the indicated aqueous acid. c 5 equiv. of metal salt were used. hexT 7 ¼ 5 0 -AcN-(CH 2 ) 6 -TTT TTT-3 0 -CPG, TC 8 ¼ 5 0 -TTC CTC TCC T-3 0 -CPG, ATC 9 ¼ 5 0 -TTA CTA CCT A-3 0 -CPG, ATGC 10 ¼ 5 0 -GTC ATG ATC T-3 0 -CPG, ACN ¼ acetonitrile, MeOH ¼ methanol. This journal is View Article Online c 1000 equiv. of amine 12 were used. d Yb(OTf) 3 was used instead of ZnCl 2 . e The 2 nd step of the reaction was performed overnight at 35 C. 10mer ATGC ¼ 5 0 -GTC ATG ATC T-3 0 , ACN ¼ acetonitrile. This journal isFig. 7 Cheminformatics analysis: A ¼ PCA plot of the DA-1(red), P (blue) and B (green) lib...

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Section: Cheminformatics Analysis Of Simulated Encoded Heterocycle LIsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

et al. 2019

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“…MCRs proved to be compatible with solid-phase synthesis and can be effective for creating scaffold diversity with a low synthetic cost ( Rivera et al, 2021 ). In 2019, Brunschweiger’s team reported isocyanide-involved MCRs for DNA-encoded combinatorial synthesis ( Kunig et al, 2019 ). This concept has great potential to be applied for fluorescence labeling or other derivatizations of DNA with isocyanides as well as to introduce an isocyano group into DNA.…”

Section: Methods To Introduce the Isocyano Group Into Biomacromoleculesmentioning

confidence: 99%

Isocyanides: Promising Functionalities in Bioorthogonal Labeling of Biomolecules

2021

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Isocyanides have drawn increasing attention in biological applications due to their attractive properties and unique reactivities, which can undergo various reactions, such as multicomponent reactions, α-addition reactions, [4 + 1] cycloaddition reactions, and the reaction scope keeps expanding. In addition to acting as reactants for the preparation of structurally interesting and diverse N-heterocycles or peptidomimetics, this type of functionality may be a good choice in the labeling and modulation of biomolecules due to the high biocompatibility and small size to minimize modifications on the parent molecule. It has been demonstrated that isocyanides can participate in biomolecule labeling through three strategies, including the two-component bioorthogonal reaction, multicomponent reaction, and metal chelation. Among them, the isocyanide-tetrazine reaction has been better studied recently, augmenting the potency of isocyanide as a bioorthogonal handle. This review will focus on the recent progress in isocyanide chemistry for labeling of biomolecules. Meanwhile, methods to introduce isocyano groups into biomacromolecules are also described to facilitate wider applications of this unique functionality.

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“…10a) 85 . In cooperation with Dömling's group 84 , the same team also exploited the versatility of isocyanide-based MCRs 10 to produce DNA-coupled heterocycles such as oxadiazoles and tetrazoles (Fig. 10a).…”

Section: Functionalized Water-stable Parallel β-Sheetsmentioning

confidence: 99%

On-resin multicomponent protocols for biopolymer assembly and derivatization

et al. 2021

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MCRs are versatile convergent procedures that incorporate 50 three or more reactants into a final product, with the consequent 51 generation of higher levels of molecular complexity and diversity 52 than other traditional organic reactions using a similar synthetic 53 effort [10][11][12][13] . They have been employed in almost all areas 54 of chemical synthesis [10][11][12][14][15][16] , but their applications in drug 55 discovery and development have unquestionable dominated the 56 interest of the chemical community 10,17,18 . MCRs are especially 57 well suited for the construction of heterocyclic-often medic-58 inally privileged-scaffolds, a task where they are comparable to 59 cycloaddition reactions in terms of scope and chemical effi-60 ciency. Indeed, solution-phase protocols are predominant in 61 both the development of new multicomponent processes and 62 the implementation of known MCRs to synthesize bioactive 63 molecules 10-18 . However, solid-phase synthesis also gained Q5 Q6

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Isocyanide Multicomponent Reactions on Solid-Phase-Coupled DNA Oligonucleotides for Encoded Library Synthesis

Cited by 64 publications

References 53 publications

Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions

Isocyanides: Promising Functionalities in Bioorthogonal Labeling of Biomolecules

On-resin multicomponent protocols for biopolymer assembly and derivatization

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