{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:05:13Z","timestamp":1784264713371,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Research, Innovation, and Digitalization","award":["108\/31.07.23"],"award-info":[{"award-number":["108\/31.07.23"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>The cysteine-based thiol\u2013epoxy \u2018click\u2019 reaction is demonstrated as an efficient and practical approach for the synthesis of zwitterionic structures. The transformation employs unprotected cysteine, proceeds in aqueous media, and affords quantitative conversions. Notably, acid- and base-catalyzed conditions provide exclusive access to different cysteine-based thioether regioisomers in aqueous conditions. The pH-responsive behavior of the resulting zwitterions is further elucidated by NMR spectroscopy. Finally, the synthetic strategy is extended to the preparation of cysteine- and glutathione-functionalized polyethylene glycol polymers, showcasing its utility for the preparation of amino acid-\/peptide-containing macromolecular materials.<\/jats:p>","DOI":"10.3390\/polym18141735","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:05:07Z","timestamp":1784163907000},"page":"1735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Regiochemical Control in a Thiol\u2013Epoxy \u2018Click\u2019 Reaction: Synthesis of Cysteine and Glutathione Chain-End Functionalized Polyethylene Glycols"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0325-970X","authenticated-orcid":false,"given":"Oana","family":"Grad","sequence":"first","affiliation":[{"name":"National Institute for Research and Development of Isotopic and Molecular Technologies\u2014INCDTIM, 67-103 Donat Street, 400293 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0676-2706","authenticated-orcid":false,"given":"Crina","family":"Socaci","sequence":"additional","affiliation":[{"name":"National Institute for Research and Development of Isotopic and Molecular Technologies\u2014INCDTIM, 67-103 Donat Street, 400293 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela Diana","family":"Lazar","sequence":"additional","affiliation":[{"name":"National Institute for Research and Development of Isotopic and Molecular Technologies\u2014INCDTIM, 67-103 Donat Street, 400293 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2313-9350","authenticated-orcid":false,"given":"Adrian","family":"P\u00eern\u0103u","sequence":"additional","affiliation":[{"name":"National Institute for Research and Development of Isotopic and Molecular Technologies\u2014INCDTIM, 67-103 Donat Street, 400293 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anzar","family":"Khan","sequence":"additional","affiliation":[{"name":"National Institute for Research and Development of Isotopic and Molecular Technologies\u2014INCDTIM, 67-103 Donat Street, 400293 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1002\/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5","article-title":"Click Chemistry: Diverse Chemical Function from a Few Good Reactions","volume":"40","author":"Kolb","year":"2001","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1002\/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4","article-title":"A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective \u201cLigation\u201d of Azides and Terminal Alkynes","volume":"41","author":"Rostovtsev","year":"2002","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1039\/b904091a","article-title":"Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) and beyond: New Reactivity of Copper(I) Acetylides","volume":"39","author":"Hein","year":"2010","journal-title":"Chem. Soc. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5930","DOI":"10.1002\/anie.201208741","article-title":"Light-Induced Click Reactions","volume":"52","author":"Tasdelen","year":"2013","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1002\/anie.200903924","article-title":"Thiol-Ene Click Chemistry","volume":"49","author":"Hoyle","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6381","DOI":"10.1021\/ma101069c","article-title":"Nucleophile-Initiated Thiol-Michael Reactions: Effect of Organocatalyst, Thiol, and Ene","volume":"43","author":"Chan","year":"2010","journal-title":"Macromolecules"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1021\/ma801903w","article-title":"Thiol-Yne Photopolymerizations: Novel Mechanism, Kinetics, and Step-Growth Formation of Highly Cross-Linked Networks","volume":"42","author":"Fairbanks","year":"2009","journal-title":"Macromolecules"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1002\/pola.23824","article-title":"The Power of Thiol-Ene Chemistry","volume":"48","author":"Kade","year":"2010","journal-title":"J. Polym. Sci. A Polym. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1002\/pol.20210126","article-title":"Click Chemistry Strategies for the Accelerated Synthesis of Functional Macromolecules","volume":"59","author":"Geng","year":"2021","journal-title":"J. Polym. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.addr.2008.02.004","article-title":"Efficient Construction of Therapeutics, Bioconjugates, Biomaterials and Bioactive Surfaces Using Azide-Alkyne \u201cClick\u201d Chemistry","volume":"60","author":"Lutz","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15998","DOI":"10.1021\/ja054114s","article-title":"Ruthenium-Catalyzed Cycloaddition of Alkynes and Organic Azides","volume":"127","author":"Zhang","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14726","DOI":"10.1021\/acs.chemrev.6b00466","article-title":"Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications","volume":"116","author":"Johansson","year":"2016","journal-title":"Chem. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Agouram, N., El Hadrami, E.M., and Bentama, A. (2021). 1,2,3-Triazoles as Biomimetics in Peptide Science. Molecules, 26.","DOI":"10.3390\/molecules26102937"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11975","DOI":"10.1039\/c2cc36566a","article-title":"Design and Synthesis of Regioisomeric Triazole Based Peptidomimetic Macrocycles and Their Dipole Moment Controlled Self-Assembly","volume":"48","author":"Ghorai","year":"2012","journal-title":"Chem. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102022","DOI":"10.1016\/j.progpolymsci.2025.102022","article-title":"Thiol-Epoxy \u2018Click\u2019 Reaction in Polymer Synthesis","volume":"169","author":"Khan","year":"2025","journal-title":"Prog. Polym. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1080\/10601325.2021.1984849","article-title":"Poly (\u00df-hydroxy thioether)s: Synthesis through thiol-epoxy \u2018click\u2019reaction and post-polymerization modification to main-chain polysulfonium salts","volume":"59","author":"Stuparu","year":"2022","journal-title":"J. Macromol. Sci. A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1002\/pola.28195","article-title":"Thiol-epoxy \u201cclick\u201d chemistry: Application in preparation and postpolymerization modification of polymers","volume":"54","author":"Stuparu","year":"2016","journal-title":"J. Polym. Sci. Part A Polym. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"43961","DOI":"10.1039\/C5RA05820A","article-title":"Multiply functionalized dendrimers: Protective-group-free synthesis through sequential thiol-epoxy \u2018click\u2019 chemistry and esterification reaction","volume":"5","author":"Gadwal","year":"2015","journal-title":"RSC Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1021\/acsmacrolett.4c00167","article-title":"Impact of a lightly branched star polyelectrolyte architecture on polyelectrolyte complexes","volume":"13","author":"Stevens","year":"2024","journal-title":"ACS Macro. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1021\/acsami.0c19405","article-title":"A modular strategy for functional pressure sensitive adhesives","volume":"13","author":"Lee","year":"2021","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1021\/acs.biomac.9b01065","article-title":"Modification of poly (5, 6-epoxy-l-norleucine) gives functional polypeptides with alternative side-chain linkages","volume":"21","author":"Perlin","year":"2019","journal-title":"Biomacromolecules"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1039\/C9PY01144G","article-title":"Functionalization-induced self-assembly under ambient conditions via thiol-epoxide \u201cclick\u201d chemistry","volume":"11","author":"Howe","year":"2020","journal-title":"Polym. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1038\/s41428-019-0244-x","article-title":"Preparation of multifunctional glycopolymers using double orthogonal reactions and the effect of electrostatic groups on the glycopolymer\u2013lectin interaction","volume":"51","author":"Oh","year":"2019","journal-title":"Polym. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"113455","DOI":"10.1016\/j.eurpolymj.2024.113455","article-title":"Tailoring copolymer architectures and macromolecular interactions for enhanced nanotherapeutic delivery: A design-by-architecture approach","volume":"220","author":"Porello","year":"2024","journal-title":"Eur. Polym. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1021\/bm5001197","article-title":"Amphipathic homopolymers for siRNA delivery: Probing impact of bifunctional polymer composition on transfection","volume":"15","author":"Buerkli","year":"2014","journal-title":"Biomacromolecules"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3534","DOI":"10.1021\/acs.biomac.1c00627","article-title":"Main-chain polysulfonium salts: Development of non-ammonium antibacterial polymers similar in their activity to antibiotic drugs vancomycin and kanamycin","volume":"22","author":"Oh","year":"2021","journal-title":"Biomacromolecules"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11191","DOI":"10.1039\/c3cc45859h","article-title":"Designing functionalizable hydrogels through thiol\u2013epoxy coupling chemistry","volume":"49","author":"Cengiz","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1002\/pola.28156","article-title":"Injectable thiol-epoxy \u201cclick\u201d hydrogels","volume":"54","author":"Gao","year":"2016","journal-title":"J. Polym. Sci. Part A Polym. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"25936","DOI":"10.1021\/acsami.8b07167","article-title":"Thiol-epoxy \u201cclick\u201d chemistry to engineer cytocompatible PEG-based hydrogel for siRNA-mediated osteogenesis of hMSCs","volume":"10","author":"Huynh","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4949","DOI":"10.1039\/D1SC00602A","article-title":"Aggregation-free and high stability core\u2013shell polymer nanoparticles with high fullerene loading capacity, variable fullerene type, and compatibility towards biological conditions","volume":"12","author":"Eom","year":"2021","journal-title":"Chem. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1021\/acspolymersau.5c00007","article-title":"Photopolymerization Using Thiol\u2013Epoxy \u2018Click\u2019 Reaction: Anionic Curing through Photolatent Superbases","volume":"5","author":"Khan","year":"2025","journal-title":"ACS Polym. Au"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1021\/jacs.9b11958","article-title":"Photoinduced proton-transfer polymerization: A practical synthetic tool for soft lithography applications","volume":"142","author":"Yeo","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1038\/s41563-022-01392-1","article-title":"Optimized design of block copolymers with covarying properties for nanolithography","volume":"21","author":"Feng","year":"2022","journal-title":"Nat. Mater."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11028","DOI":"10.1039\/D3CC02555A","article-title":"Thiol-Epoxy \u2018Click\u2019 Chemistry: A Focus on Molecular Attributes in the Context of Polymer Chemistry","volume":"59","author":"Khan","year":"2023","journal-title":"Chem. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wang, H., Cheng, K., Zheng, H., Zhao, X., Chen, D., Tian, X., Sun, J., Cheng, Y., Lang, L., and Bao, S. (2026). Zwitterionic Polymers: Synthesis, Architectures, Properties and Biomedical Applications. Adv. Mater., e73461.","DOI":"10.1002\/adma.73461"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1039\/C4PY01556H","article-title":"Synthesis and Characterization of Poly(Amino Acid Methacrylate)-Stabilized Diblock Copolymer Nano-Objects","volume":"6","author":"Ladmiral","year":"2015","journal-title":"Polym. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9404","DOI":"10.1021\/ja503400r","article-title":"Zwitterionic Poly(amino acid methacrylate) Brushes","volume":"136","author":"Alswieleh","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2016.08.039","article-title":"Crossing the Blood-Brain Barrier: Glutathione-Conjugated Poly(Ethylene Imine) for Gene Delivery","volume":"241","author":"Englert","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1007\/s00044-024-03225-z","article-title":"Glutathione Transporter as a Target for Brain Drug Delivery","volume":"33","author":"Guan","year":"2024","journal-title":"Med. Chem. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1039\/D2OB02262A","article-title":"Thia-Michael Addition: The Route to Promising Opportunities for Fast and Cysteine-Specific Modification","volume":"21","author":"Ahangarpour","year":"2023","journal-title":"Org. Biomol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17291","DOI":"10.1021\/ja307788u","article-title":"Facile and General Preparation of Multifunctional Main-Chain Cationic Polymers through Application of Robust, Efficient, and Orthogonal Click Chemistries","volume":"134","author":"Saha","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/pi.6278","article-title":"Side-Chain Amino-Acid-Based Polymers: Self-Assembly and Bioapplications","volume":"71","author":"Nayak","year":"2022","journal-title":"Polym. Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1002\/pola.28575","article-title":"Established and Emerging Strategies for Polymer Chain-End Modification","volume":"55","author":"Lunn","year":"2017","journal-title":"J. Polym. Sci. A Polym. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"102003","DOI":"10.1016\/j.progpolymsci.2025.102003","article-title":"Polymer Chain-End Chemistry: Unlocking next-Generation Functional Materials","volume":"168","author":"Lee","year":"2025","journal-title":"Prog. Polym. Sci."}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/18\/14\/1735\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:20:14Z","timestamp":1784262014000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/18\/14\/1735"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":44,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["polym18141735"],"URL":"https:\/\/doi.org\/10.3390\/polym18141735","relation":{},"ISSN":["2073-4360"],"issn-type":[{"value":"2073-4360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]}}}