Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors.

  title={Design, synthesis, and evaluation of cystargolide-based $\beta$-lactones as potent proteasome inhibitors.},
  author={Doleshwar Niroula and Liam P. Hallada and Camille Le Chapelain and Susantha K Ganegamage and Devon Dotson and Snezna Rogelj and Michael Groll and Rodolfo Tello-Aburto},
  journal={European journal of medicinal chemistry},
3 Citations
Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors.
Natural product scaffolds as inspiration for the design and synthesis of 20S human proteasome inhibitors
The following review discusses the efforts made in the field to isolate and identify natural products as inhibitors of the proteasome and some of the modifications made to natural products in order to discover more potent and selective inhibitors for potential disease treatment.
Four-Membered Ring Systems


A Minimal β-Lactone Fragment for Selective β5c or β5i Proteasome Inhibitors.
Broad-spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here
Total synthesis and biological activity of lactacystin, omuralide and analogs.
  • E. Corey, W. Li
  • Chemistry, Biology
    Chemical & pharmaceutical bulletin
  • 1999
It is concluded that 1 and 2 are nearly optimal for the irreversible inactivation of the 20 S proteasome.
Cystargolides, 20S Proteasome Inhibitors Isolated from Kitasatospora cystarginea.
Two novel β-lactone-containing natural products, cystargolides A and B, were isolated from the actinomycete Kitasatospora Cystarginea using a methodology associating liquid chromatography-high-resolution mass spectrometry (LC-HRMS) analysis and the statistical analysis tool principal component analysis (PCA).
Structural analysis of spiro beta-lactone proteasome inhibitors.
Structural data support the hypothesis that the discrepancy in potency between Lactone 4 and 5 may be due to differences in the hydrolytic stabilities of the resulting acyl enzyme complexes.
Systematic comparison of peptidic proteasome inhibitors highlights the α-ketoamide electrophile as an auspicious reversible lead motif.
This study was able to introduce and characterize the class of α-ketoamides as the most potent reversible inhibitors with possible applications for the therapy of solid tumors as well as autoimmune disorders.
Nature of Pharmacophore Influences Active Site Specificity of Proteasome Inhibitors*
It is reported that active site specificity of inhibitors can also be tuned by the chemical nature of the pharmacophore, and replacement of the epoxyketone by vinyl sulfone moieties further improves the selectivity of β5-specific inhibitors NC-005, YU-101, and PR-171 (carfilzomib).
Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes.
The development of cell-permeable β1i and β5i selective inhibitors that outperform existing leads in terms of selectivity and/or potency are reported.
Systematic Analyses of Substrate Preferences of 20S Proteasomes Using Peptidic Epoxyketone Inhibitors.
Detailed picture of the substrate and ligand specificities of proteasomes is delineated and will further guide drug development efforts toward subunit-specific proteasome inhibitors for applications as diverse as cancer and autoimmune disorders.
Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin
Lactacystin appears to modify covalently the highly conserved amino-terminal threonine of the mammalian proteasome subunit X (also called MB1), a close homolog of the LMP7 proteasom subunit encoded by the major histocompatibility complex and may have a catalytic role.
Biosynthesis of the β-Lactone Proteasome Inhibitors Belactosin and Cystargolide.
Feeding experiments with isotope-labeled precursors and in’vitro biochemistry showed that the formation of the β-lactone warhead is unprecedented and reminiscent of leucine biosynthesis, and that it involves the action of isopropylmalate synthase homologues.