Multi-tiered chemical proteomic maps of tryptoline acrylamide–protein interactions in cancer cells

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(10), P. 1592 - 1604

Published: Aug. 13, 2024

Language: Английский

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Rh(iii)-catalyzed sp³/sp²–C–H heteroarylations via cascade C–H activation and cyclization

Chemical Science, Journal Year: 2024, Volume and Issue: 15(17), P. 6544 - 6551

Published: Jan. 1, 2024

A Rh( iii )-catalyzed C–H indolation of 8-methylquinolines was illustrated with 2-alkynylanilines via sp 3 activation to achieve indole-tethered quinoline derivatives. Extension this methodology quinoline- N -oxide led biologically relevant oxindolyl-quinolines.

Language: Английский

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DNA-compatible one-pot synthesis of multi-substituted dihydrofuran via pyridinium ylide-mediated cyclization

Organic & Biomolecular Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Synthesis of chemically diverse heterocyclic scaffolds in DNA-encoded libraries is highly demanded. We herein reported a convenient one-pot multi-component on-DNA synthetic strategy to afford multi-substituted 2,3-dihydrofuran via pyridinium ylide-mediated cyclization. This reaction exhibited modest excellent conversions for broad range DNA-conjugated aldehydes, β-ketonitriles and salts under mild conditions. Furthermore, the compatibility this with DEL construction was verified by enzymatic DNA ligation, PCR amplification mock library synthesis.

Language: Английский

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Photoinduced Site-Selective Alkylation Enabling Synthesis of C-3-Alkylated Quinoxalinone on DNA

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

A mild and biocompatible strategy for the site-selective alkylation of quinoxalinones via photoinduced dehydrogenative has been developed. This protocol enables functionalization both unprotected quinoxalinone nonreactive dihydroquinoxalinone under DNA-compatible conditions. The optimized reaction proceeds efficiently while tolerating a diverse range alkyl donors from various radical precursors. Given its simplicity DNA compatibility, this methodology offers platform construction DNA-encoded libraries incorporating privileged scaffold.

Language: Английский

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Synthesis of Thiohydantoin Scaffolds on DNA for Focused DNA-Encoded Library Construction

Organic Letters, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 3, 2024

Thiohydantoin represents a significant class of biologically active privileged heterocyclic scaffolds. Herein, we present convenient and robust DNA-compatible method for constructing thiohydantoin-focused DNA-encoded library. This reaction can be applied to wide variety isothiocyanate partners, arylamine feedstocks, diverse α-amine acid derivatives, exhibiting excellent conversions, high functional group tolerance, preservation DNA tag integrity. Our allows easy access valuable three-cycle

Language: Английский

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Evaluation of the Topology Space of DNA-Encoded Libraries

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(15), P. 4641 - 4653

Published: July 26, 2023

DNA-encoded libraries (DELs) are widely used in the discovery of drug candidates, and understanding their design principles is critical for accessing better libraries. Most DELs combinatorial nature synthesized by assembling sets building blocks specific topologies. In this study, different aspects library topology were explored effect on DEL properties chemical diversity was analyzed. We introduce a descriptor topological assignment (DELTA) use it to examine landscape possible topologies coverage literature. A generative topographic mapping analysis revealed that impact space secondary block selection. Furthermore, became apparent analyze dictates how structures cluster, with effects being when using three-dimensional descriptors but not common two-dimensional descriptors. This outcome points potential challenges attempts predict productivity based analyses alone. While rather inconsequential defining encoded compounds, greatly affects interactions target proteins as illustrated docking studies NAD/NADP binding model receptors.

Language: Английский

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Simple and Practical DNA Quantification Method for DNA-Encoded Library Synthesis

ACS Omega, Journal Year: 2023, Volume and Issue: 8(50), P. 48050 - 48055

Published: Dec. 7, 2023

Over the past three decades, DNA-encoded library (DEL) technologies have become one of most relevant strategies for hit-finding. Recent advances in synthetic methodologies libraries rendered increased chemical space available, but it is unknown how every variety chemistry affects DNA's integrity. Available assays to quantify DNA damage are restricted electrophoresis, ligation efficiency, and mostly qPCR quantification sequencing, which may contain predisposition inconsistency. We developed an external standard method through LC-MS analysis accurately throughout transformations. An assessment was conducted on on-DNA reactions that frequently employed DEL synthesis, these results were compared traditional measurements. Our study provides a simple, practicable, accurate measurement degradation during synthesis. finding reveals substantial disagreement among usual DNA-damaging methods, been largely neglected so far.

Language: Английский

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Discovery Small-Molecule p300 Inhibitors Derived from a Newly Developed Indazolone-Focused DNA-Encoded Library

Bioconjugate Chemistry, Journal Year: 2024, Volume and Issue: 35(8), P. 1251 - 1257

Published: Aug. 8, 2024

The DNA-encoded library (DEL) is a robust tool for chemical biology and drug discovery. In this study, we developed DNA-compatible light-promoted reaction that highly efficient plate-compatible DEL construction based on the formation of indazolone scaffold. Employing high-efficiency approach, constructed featuring an core, which enabled identification novel series ligands specifically targeting E1A-binding protein (p300) after selection. Taken together, our findings underscore feasibility reactions in synthesis unveil promising avenues developing p300-targeting inhibitors.

Language: Английский

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Challenges and Prospects of DNA-Encoded Library Data Interpretation

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(22), P. 12551 - 12572

Published: Nov. 7, 2024

DNA-encoded library (DEL) technology is a powerful platform for the efficient identification of novel chemical matter in early drug discovery process enabled by parallel screening vast libraries encoded small molecules through affinity selection and deep sequencing. While DEL selections provide rich data sets computational discovery, underlying technical factors influencing remain incompletely understood. This review systematically examines key parameters affecting information their impact on hit triaging machine learning integration. The need rigorous handling interpretation emphasized, with standardized methods being critical success DEL-based approaches. Major challenges include relationship between sequence counts binding affinities, frequent hitters, influence such as inhomogeneous composition, DNA damage, linkers modes. Experimental artifacts, those caused protein immobilization matrix effects, further complicate interpretation. Recent advancements using to denoise predict candidates are highlighted. offers practical guidance adopting best practices integrating robust methodologies, comprehensive analysis, tools improve accuracy efficacy DEL-driven discovery.

Language: Английский

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On-DNA Mannich Reaction for DNA-Encoded Library Synthesis

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 89(22), P. 16957 - 16963

Published: Nov. 1, 2024

The β-amino ketones produced through the Mannich reaction hold significant potential as candidates for various drugs. In this study, we optimized on-DNA conditions and applied them to investigate reactions of DNA-conjugated aldehydes with amine ketone building blocks. developed preserved DNA integrity established viable routes library production. These results underscore in DNA-encoded (DEL) synthesis.

Language: Английский

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