Convergent Synthesis and Biological Evaluation of Syringolin A and Derivatives as Eukaryotic 20S Proteasome Inhibitors

• Published in: European Journal of Organic Chemistry Vol. 2010; no. 21; pp. 3991 - 4003
• Main Authors: Clerc, Jérôme, Schellenberg, Barbara, Groll, Michael, Bachmann, André S., Huber, Robert, Dudler, Robert, Kaiser, Markus
• Format: Book Review Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.07.2010; WILEY‐VCH Verlag; Wiley; Wiley-VCH
• Subjects: Biological activity; Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Inhibitors; Metathesis; Natural products; Organic chemistry; Peptides; Physical Sciences; Preparations and properties; Science & Technology; Synthetic methods; YEAST; POTENT; Inhibitors; TMC-95A ANALOGS; Natural products; ACIDS; Metathesis; ESTERS; Synthetic methods; PV.-SYRINGAE; CLEAVAGE; Biological activity; Peptides; Nitrogen heterocycle; Natural compound; Macrocycle; Ethylene oxide polymer; Side chain; Cyclization; Functionalization; Analog; Proteasome inhibitor; Proteasome endopeptidase complex; Ureas; Inhibition; Chemical synthesis; Conformation
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201000317

A convergent synthesis of SylA was developed and consists of the synthesis of a fully functionalized macrocycle, which is subsequently coupled with a urea moiety. For cyclization, ring‐closing metathesis of a conformationally preorganized precursor was employed. The established synthetic route was then applied to the synthesis of SylA derivatives by using various peptidic side chains for decoration of the SylA macrocycle. The resulting collection of SylA analogues was tested for proteasome inhibition, revealing PEGylated SylA derivatives as the most potent proteasome inhibitors. A convergent synthesis to SylA and derivatives was developed and employed for the synthesis of a small collection of SylA analogues. The critical key step is ring‐closing metathesis of a preorganized precursor, yielding a fully functionalized SylA macrocycle for further decoration with various side chains. The biological activities of these compounds were tested.