Substrate-guided optimization of the syringolins yields potent proteasome inhibitors with activity against leukemia cell lines.

@article{Totaro2015SubstrateguidedOO,
  title={Substrate-guided optimization of the syringolins yields potent proteasome inhibitors with activity against leukemia cell lines.},
  author={Kyle A Totaro and Dominik Barthelme and Peter T. Simpson and Robert T. Sauer and Jason K. Sello},
  journal={Bioorganic \& medicinal chemistry},
  year={2015},
  volume={23 18},
  pages={
          6218-22
        }
}
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References

SHOWING 1-10 OF 29 REFERENCES
Total synthesis of syringolin A and improvement of its biological activity.
TLDR
The development process for syringolin A analogues having improved proteasome inhibitory and antitumor activity is described, and these biological properties are comparable to those of bortezomib, a clinically used first-line proteasomesome inhibitor.
Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition
TLDR
The total synthesis of syringolin A and B was described, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins.
Syringolin B-inspired proteasome inhibitor analogue TIR-203 exhibits enhanced biological activity in multiple myeloma and neuroblastoma
TLDR
The newly designed proteasome inhibitor TIR-203 is more potent than the natural product SylA and strongly inhibits the cell viability and proteasomal activity of MM and NB cells.
Convergent Synthesis and Biological Evaluation of Syringolin A and Derivatives as Eukaryotic 20S Proteasome Inhibitors
TLDR
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, revealing PEGylated SylA derivatives as the most potent proteasome inhibitors.
Exploiting nature's rich source of proteasome inhibitors as starting points in drug development.
TLDR
This review highlights the important role of the structural elucidation of the various unique binding mechanisms of these compounds that have been optimized throughout evolution to target the proteasome in finding potential drugs with reduced off-target activities.
Development of the Proteasome Inhibitor Velcade™ (Bortezomib)
TLDR
A novel pharmacodynamic assay has shown that bortezomib–mediated proteasome blockade is dose-dependent and reversible, and phase II trials have been initiated for both solid and hematological malignancies.
The natural product hybrid of Syringolin A and Glidobactin A synergizes proteasome inhibition potency with subsite selectivity.
The preparation of a Syringolin A/Glidobactin A hybrid (SylA-GlbA) consisting of a SylA macrocycle connected to the GlbA side chain and its potent proteasome targeting of all three proteasomal
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