A hydrophobic photouncaging reaction to profile the lipid droplet interactome in tissues

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(16)

Published: April 16, 2025

Most bioorthogonal photouncaging reactions preferentially occur in polar environments to accommodate biological applications the aqueous cellular milieu. However, they are not precisely designed chemically adapt diverse microenvironments of cell. Herein, we report a hydrophobic reaction with tailored photolytic kinetics toward solvent polarity. Structural modulations aminobenzoquinone-based photocage reveal impact cyclic ring size, steric substituent, and electronic substituent on individual uncaging ( k H2O dioxane ) polarity preference / ). Rational incorporation optimized moieties leads up 20.2-fold nonpolar kinetic selectivity Further photochemical spectroscopic characterizations theoretical calculations together uncover mechanism underlying polarity-dependent kinetics. The uncaged ortho-quinone methide product bears covalent reactivity nucleophiles protein revealed by tandem mass spectrometry. Finally, demonstrate application such lipophilic chemistry selective labeling profiling proteins proximity lipid droplets inside human fatty liver tissues. Together, this work studies effects adapts it suborganelle-targeted profiling.

Language: Английский

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2 From Biological Chemistry to Bioorthogonal Reactions

Published: Jan. 1, 2025

Abstract This contribution aims to trace the origins of bioorthogonal chemistry, from its roots in early alchemy and Scientific Revolution, development as a response quest understand fundamental principles life. The application chemical tools study manipulate biological processes biomolecules laid foundation for modern biology. With advent first reactions that proceed selectively efficiently without interfering with systems, scientists gained unique set achieve an unprecedented level understanding at molecular level. New techniques such strain-promoted azide–alkyne cycloaddition (SPAAC), tetrazine ligation, artificial metalloenzymes have further advanced field. These chemistry significantly extended potential hold promise revolutionizing healthcare through improved drug delivery diagnostic tools. By placing these achievements context history science, it is clear this field has bright future. As our deepens technology evolves, we can anticipate their incorporation into wide range practices, potentially ushering new era personalized treatments.

Language: Английский

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Palladium-Mediated Bioorthogonal System for Prodrug Activation of N-Benzylbenzamide-Containing Tubulin Polymerization Inhibitors for the Treatment of Solid Tumors

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19905 - 19924

Published: Nov. 1, 2024

Bioorthogonal cleavage reactions have been developed as an intriguing strategy to enhance the safety of chemotherapeutics. Aiming reduce toxicity and improve targeted release properties colchicine binding site inhibitors (CBSIs) based on previous work, a series biologically inert prodrugs were further designed synthesized through bioorthogonal prodrug strategy. The therapeutic effects could be "turned-on" once combined with palladium resins. Particularly, 2b was 68.3-fold less cytotoxic compared parent compound, while its cytotoxicity recovered in situ presence Mechanism studies confirmed that inhibited cell growth same manner CBSIs. More importantly, vivo efficacy demonstrated efficient activation by resins, resulting significant inhibition tumor (63.2%). These results suggest improved property catalyzed Pd-mediated reaction deserves investigation.

Language: Английский

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Recent advances in porous molecular cages for photocatalytic organic conversions

Dalton Transactions, Journal Year: 2023, Volume and Issue: 52(42), P. 15216 - 15232

Published: Jan. 1, 2023

Photocatalytic organic conversion is considered an efficient, environmentally friendly, and energy-saving strategy for synthesis. Porous molecular cages exhibit significant potential in the realm of photocatalytic conversion.

Language: Английский

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Accessing Functionalized Tetrazines as Click Chemistry Tools: A Synthesis Guide for Chemists and Chemical Biologists

European Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 27(3)

Published: Nov. 30, 2023

Abstract Since the first report that 1,2,4,5‐tetrazines undergo a bioorthogonal reaction with dienophiles in form of an inverse electron‐demand Diels‐Alder reaction, demand for high‐yielding synthetic approaches towards them grew steadily. Despite this significant interest, tetrazines were predominantly accessed via Pinner synthesis or other Pinner‐like reactions, significantly limiting available substrates. In particular, unsymmetrically substituted s‐tetrazines selective conjugation to another species presented major challenge. To tackle these challenges, new and innovative transformations have been developed widen scope accessible symmetric unsymmetric tetrazines. For instance, Ni(II), Zn(II), sulphur‐catalysed reactions between two nitriles hydrazine developed, which provide access wide range (un‐)symmetric aryl s‐tetrazines. Also, amidines orthoesters give alkyl substituents, whereas usage CH 2 Cl yields valuable H‐monosubstituted Methods using thiocarbohydrazides, terminal fluoroolefins, oxetane esters, tosyl hydrazones are among recent additions. Due high interest tetrazine click‐chemistry approaches, some reach beyond we expect overview routes aid exploration further applications Ultimately, hope guide chemists chemical biologists accessing functional

Language: Английский

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