Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

SUBMITTER: Pels K

PROVIDER: S-EPMC7000991 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

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

Pels Kevin K Dickson Paige P An Hongchan H Kodadek Thomas T

ACS combinatorial science 20180117 2

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 traditi ...[more]

PMID: 29298042

Similar Datasets

Solid-Phase Synthesis of ?-Amino Ketones Via DNA-Compatible Organocatalytic Mannich Reactions.

Project description:One-bead-one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are comprised of oligoamides, particularly peptides, peptoids, and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Toward this end, we report here the efficient proline-catalyzed asymmetric Mannich reaction between immobilized aldehydes and soluble ketones and anilines. The reaction conditions do not compromise the amplification of DNA by the PCR. Thus, this chemistry will likely be useful for the construction of novel DNA-encoded libraries by solid-phase synthesis.

| S-EPMC7074847 | biostudies-literature

Solid-Phase Synthesis of ?-Hydroxy Ketones Via DNA-Compatible Organocatalytic Aldol Reactions.

Project description:One-bead one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are composed of oligoamides, particularly peptides, peptoids, and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Toward this end, we report here that the proline-catalyzed asymmetric aldol reaction, developed by List and Barbas for solution-phase synthesis, also works well for coupling immobilized aldehydes and soluble ketones. These reaction conditions do not compromise the amplification of DNA by the polymerase chain reaction. Thus, this chemistry should be useful for the construction of novel DNA-encoded OBOC libraries by solid-phase synthesis.

| S-EPMC6826340 | biostudies-literature

Resin capsules: permeable containers for parallel/combinatorial solid-phase organic synthesis.

Project description:A resin capsule is a permeable container for resin beads designed for multiple/combinatorial solid-phase organic synthesis. Resin capsules consist of a high density polyethylene ring sealed with peek mesh on both sides. The cylindrical shape of resin capsules enabled space-saving packing into plastic columnlike reaction vessels commonly used for solid-phase organic synthesis. Resin capsules have been evaluated for their use in combinatorial synthesis, and a set of model compounds with excellent purity was prepared.

| S-EPMC2652863 | biostudies-literature

DNA display III. Solid-phase organic synthesis on unprotected DNA.

Project description:DNA-directed synthesis represents a powerful new tool for molecular discovery. Its ultimate utility, however, hinges upon the diversity of chemical reactions that can be executed in the presence of unprotected DNA. We present a solid-phase reaction format that makes possible the use of standard organic reaction conditions and common reagents to facilitate chemical transformations on unprotected DNA supports. We demonstrate the feasibility of this strategy by comprehensively adapting solid-phase 9-fluorenylmethyoxycarbonyl-based peptide synthesis to be DNA-compatible, and we describe a set of tools for the adaptation of other chemistries. Efficient peptide coupling to DNA was observed for all 33 amino acids tested, and polypeptides as long as 12 amino acids were synthesized on DNA supports. Beyond the direct implications for synthesis of peptide-DNA conjugates, the methods described offer a general strategy for organic synthesis on unprotected DNA. Their employment can facilitate the generation of chemically diverse DNA-encoded molecular populations amenable to in vitro evolution and genetic manipulation.

| S-EPMC434150 | biostudies-literature

Aryl diazonium intermediates enable mild DNA-compatible C-C bond formation for medicinally relevant combinatorial library synthesis.

Project description:Forging carbon-carbon (C-C) linkage in DNA-encoded combinatorial library synthesis represents a fundamental task for drug discovery, especially with broad substrate scope and exquisite functional group tolerance. Here we reported the palladium-catalyzed Suzuki-Miyaura, Heck and Hiyama type cross-coupling via DNA-conjugated aryl diazonium intermediates for DNA-encoded chemical library (DEL) synthesis. Starting from commodity arylamines, this synthetic route facilely delivers vast chemical diversity at a mild temperature and pH, thus circumventing damage to fragile functional groups. Given its orthogonality with traditional aryl halide-based cross-coupling, the aryl diazonium-centered strategy expands the compatible synthesis of complex C-C bond-connected scaffolds. In addition, DNA-tethered pharmaceutical compounds (e.g., HDAC inhibitor) are constructed without decomposition of susceptible bioactive warheads (e.g., hydroxamic acid), emphasizing the superiority of the aryl diazonium-based approach. Together with the convenient transformation into an aryl azide photo-crosslinker, aryl diazonium's DNA-compatible diversification synergistically demonstrated its competence to create medicinally relevant combinatorial libraries and investigate protein-ligand interactions in pharmaceutical research.

| S-EPMC9667928 | biostudies-literature

Solid-phase combinatorial synthesis using microarrays of microcompartments with light-induced on-chip cell screening.

Project description:The process of drug discovery includes individual synthesis and characterization of drug candidates, followed by a biological screening, which is separated from synthesis in space and time. This approach suffers from low throughput and associated high costs, which in turn lead to inefficiency in the field of drug discovery. Here, we present a miniaturized platform combining combinatorial solid-phase synthesis with high-throughput cell screenings. The method is based on the formation of nanoporous poly(2-hydroxyethyl methacrylate-co-ethylene dimethacrylate) layers patterned with hydrophilic spots separated from each other by superhydrophobic liquid-impermeable barriers. The porous polymer inside the hydrophilic spots is used as a support to conduct solid-phase synthesis. The hydrophilic spots can be then filled with droplets containing either reagents for synthesis or live cells. Upon irradiation with UV light, products of solid-phase synthesis are released from the porous polymer because of the photo-cleavable linkers used and diffuse into separate droplets. The light-induced release of the products allows the control of the release spatially, temporally, and quantitatively. To demonstrate the versatility and usability of the platform for various cell lines, we have successfully implemented peptide synthesis to create an exemplary chemical library and demonstrated high cell viability after the UV-triggered small-molecule release.

| S-EPMC7061619 | biostudies-literature

Solid-phase synthesis and screening of N-acylated polyamine (NAPA) combinatorial libraries for protein binding.

Project description:Inhibitors for protein-protein interactions are challenging to design, in part due to the unique and complex architectures of each protein's interaction domain. Most approaches to develop inhibitors for these interactions rely on rational design, which requires prior structural knowledge of the target and its ligands. In the absence of structural information, a combinatorial approach may be the best alternative to finding inhibitors of a protein-protein interaction. Current chemical libraries, however, consist mostly of molecules designed to inhibit enzymes. In this manuscript, we report the synthesis and screening of a library based on an N-acylated polyamine (NAPA) scaffold that we designed to have specific molecular features necessary to inhibit protein-protein interactions. Screens of the library identified a member with favorable binding properties to the HIV viral protein R (Vpr), a regulatory protein from HIV, that is involved in numerous interactions with other proteins critical for viral replication.

| S-EPMC2982675 | biostudies-literature

Preparation and Application of an Inexpensive α-Formylglycine Building Block Compatible with Fmoc Solid-Phase Peptide Synthesis.

Project description:α-Formylglycine (fGly) is a rare residue located in the active site of sulfatases and serves as a precursor to pharmaceutically relevant motifs. The installation of fGly motifs into peptides is currently challenging due to degradation under the acidic and nucleophile-rich conditions accompanying resin cleavage during solid-phase peptide synthesis. We report the synthesis of acid- and nucleophile-tolerant α-formylglycine building blocks from vitamin C and use them to prepare callyaerin A, a macrocyclic peptide containing an fGly-derived motif.

| S-EPMC10071478 | biostudies-literature

Solid-phase total synthesis of kahalalide A and related analogues.

Project description:The marine natural product kahalalide A, a cyclic depsipeptide, was prepared by total synthesis on solid-phase. A backbone cyclization strategy was followed, using the Kenner sulfonamide safety-catch linker. By NMR comparison of synthetic and naturally isolated material, the stereochemistry of the methylbutyrate side chain was established as (S). Several analogues were synthesized and tested for antimycobacterial activity. The results indicate that the alcohol functional group in the serine and threonine residues is important, while the methylbutyrate side chain can be replaced by an achiral hexanoate with an increase in activity.

| S-EPMC4917212 | biostudies-literature

Considerations for Achieving Maximized DNA Recovery in Solid-Phase DNA-Encoded Library Synthesis.

Project description:DNA-encoded library (DEL) technology enables rapid, economical synthesis, and exploration of novel chemical space. Reaction development for DEL synthesis has recently accelerated in pace with a specific emphasis on ensuring that the reaction does not compromise the integrity of the encoding DNA. However, the factors that contribute to a reaction's "DNA compatibility" remain relatively unknown. We investigated several solid-phase reactions and encoding conditions and determined their impact on DNA compatibility. Conditions that minimized the accessibility of reactive groups on the DNA encoding tag (switching solvent, low temperature, double-stranded encoding tag) significantly improved compatibility. We showcased this approach in the multistep synthesis of an acyldepsipeptide (ADEP1) fragment, which preserved 73% of DNA for a >100-fold improvement over canonical conditions. These results are particularly encouraging in the context of multistep reaction sequences to access natural product-like scaffolds and more broadly underscore the importance of reconciling the biophysical properties and reactivity of DNA with chemistry development to yield high-quality libraries of those scaffolds.

| S-EPMC7655546 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data