Tunable heteroaromatic nitriles for selective bioorthogonal click reaction with cysteine

Proj, Matic (author), Strašek Benedik, Nika (author), Pajk, Stane (author), Knez, Damijan (author), Sosič, Izidor (author)

The binucleophilic properties of 1,2-aminothiol and its rare occurrence in nature make it a useful reporter for tracking molecules in living systems. The 1,2-aminothiol moiety is present in cysteine, which is a substrate for a biocompatible click reaction with heteroaromatic nitriles. Despite the wide range of applications for this reaction, the scope of nitrile substrates has been explored only to a limited extent. In this study, we expand the chemical space of heteroaromatic nitriles for bioconjugation under physiologically relevant conditions. We systematically assembled a library of 116 2-cyanobenzimidazoles, 1-methyl-2-cyanobenzimidazoles, 2-cyanobenzothiazoles, and 2-cyanobenzoxazoles containing electron-donating and electron-withdrawing substituents at all positions of the benzene ring. The compounds were evaluated for their stability, reactivity, and selectivity toward the N-terminal cysteine of model oligopeptides. In comparison to the benchmark 6-hydroxy-2-cyanobenzothiazole or 6-amino-2-cyanobenzothiazole, we provide highly selective and moderately reactive nitriles as well as highly reactive yet less selective analogs with a variety of enabling attachment chemistries to aid future applications in bioconjugation, chemical biology, and nanomaterial science.

• Language: English
• Keywords: labeling, monomers, nitrogen compounds, peptides, reactivity, proteins
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 1271–1281
• Numbering: Vol. 34, iss. 7
• PID: 20.500.12556/RUL-148256
• UDC: 615.4:54
• ISSN on article: 1043-1802
• DOI: 10.1021/acs.bioconjchem.3c00163
• COBISS.SI-ID: 156888323
• Publication date in RUL: 07.08.2023

Record is a part of a journal

• Title: Bioconjugate chemistry
• Shortened title: Bioconjug. chem.
• Publisher: American Chemical Society
• ISSN: 1043-1802
• COBISS.SI-ID: 1492303

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: označevanje, monomeri, dušikove spojine, peptidi, proteini, reaktivnost, farmacevtska kemija

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Funder: ARRS - Slovenian Research Agency
• Funding programme: Young Researchers