Synthesis and biochemical evaluation of warhead-decorated psoralens as (immuno)proteasome inhibitors

Shannon Schiffrer, Eva (author), Proj, Matic (author), Gobec, Martina (author), Rejc, Luka (author), Šterman, Andrej (author), Mravljak, Janez (author), Gobec, Stanislav (author), Sosič, Izidor (author)

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure–activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.

• Language: English
• Keywords: immunoproteasome, psoralen core, non-peptidic, electrophilic compounds, warhead scan
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 18 str.
• Numbering: Vol. 26, iss. 2, art. 356
• PID: 20.500.12556/RUL-134920
• UDC: 615.4:54:616-097
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules26020356
• COBISS.SI-ID: 46540803
• Publication date in RUL: 11.02.2022

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

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.
• Licensing start date: 12.01.2021

Secondary language

• Language: Slovenian
• Keywords: imunopreoteasom, zaviralci, psoralen, avtoimunske bolezni, farmacevtska kemija