Total Synthesis of Syringolin A and Improvement of Its Biological Activity

Chiba, Takahiro; Hosono, Hidetaka; Nakagawa, Koji; Asaka, Masahiro; Takeda, Hiroshi; Matsuda, Akira; Ichikawa, Satoshi

doi:10.1002/ange.201402428

Cited by 7 publications

(4 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SylA preferentially inhibits the proteasomal ␤5 subunit (chymotrypsin-like; CT-L) activity with a K i value of 0.843 M, weakly inhibits the ␤2 subunit (trypsinlike; T-L) activity with a K i value of 6.7 M, and has no effects on the ␤1 subunit (caspase-like; C-L) activity (12,15). We previously synthesized and evaluated a number of SylA analogs (13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and three other groups have designed syringolin variants (23)(24)(25)(26). In this study, we synthesized TIR-199, one of the most potent SylA-derived compounds to date.…”

mentioning

confidence: 99%

Syrbactin Structural Analog TIR-199 Blocks Proteasome Activity and Induces Tumor Cell Death

Bachmann

Opoku-Ansah

Ibarra‐Rivera

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Multiple myeloma is an aggressive hematopoietic cancer of plasma cells. The recent emergence of three effective FDA-approved proteasome-inhibiting drugs, bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro), confirms that proteasome inhibitors are therapeutically useful against neoplastic disease, in particular refractory multiple myeloma and mantle cell lymphoma. This study describes the synthesis, computational affinity assessment, and preclinical evaluation of TIR-199, a natural product-derived syrbactin structural analog. Molecular modeling and simulation suggested that TIR-199 covalently binds each of the three catalytic subunits (␤1, ␤2, and ␤5) and revealed key interaction sites. In vitro and cell culturebased proteasome activity measurements confirmed that TIR-199 inhibits the proteasome in a dose-dependent manner and induces tumor cell death in multiple myeloma and neuroblastoma cells as well as other cancer types in the NCI-60 cell panel. It is particularly effective against kidney tumor cell lines, with >250-fold higher anti-tumor activities than observed with the natural product syringolin A. In vivo studies in mice revealed a maximum tolerated dose of TIR-199 at 25 mg/kg. The anti-tumor activity of TIR-199 was confirmed in hollow fiber assays in mice. Adverse drug reaction screens in a kidney panel revealed no off-targets of concern. This is the first study to examine the efficacy of a syrbactin in animals. Taken together, the results suggest that TIR-199 is a potent new proteasome inhibitor with promise for further development into a clinical drug for the treatment of multiple myeloma and other forms of cancer.

show abstract

mentioning

confidence: 99%

Syrbactin Structural Analog TIR-199 Blocks Proteasome Activity and Induces Tumor Cell Death

Bachmann

Opoku-Ansah

Ibarra‐Rivera

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Therefore, solid phase synthesis was applied, in which an asymmetric urea-dipeptide can be selectively and easily synthesized by a simple purification procedure (Scheme ). Fmoc- l -methionine immobilized on the 2-chlorotrityl resin was treated with piperidine, and the resulting amine was converted to the corresponding carbonylimidazolidate, which was reacted with 10 in the presence of i -Pr 2 NEt to yield urea 12 . Finally, removal of the urea-dipeptide from the resin by treatment with 1% TFA in CH 2 Cl 2 cleanly provided 4 with a 78% yield over four steps from 11 .…”

Section: Results and Discussionmentioning

confidence: 99%

Elucidating the Structural Requirement of Uridylpeptide Antibiotics for Antibacterial Activity

et al. 2020

Self Cite

View full text Add to dashboard Cite

The synthesis and biological evaluation of analogues of uridylpeptide antibiotics were described, and the molecular interaction between the 3′-hydroxy analogue of mureidomycin A (3′-hydroxymureidomycin A) and its target enzyme, phospho-MurNAc-pentapeptide transferase (MraY), was analyzed in detail. The structure−activity relationship (SAR) involving MraY inhibition suggests that the side chain at the urea-dipeptide moiety does not affect the MraY inhibition. However, the anti-Pseudomonas aeruginosa activity is in great contrast and the urea-dipeptide motif is a key contributor. It is also suggested that the nucleoside peptide permease NppA1A2BCD is responsible for the transport of 3′-hydroxymureidomycin A into the cytoplasm. A systematic SAR analysis of the urea-dipeptide moiety of 3′-hydroxymureidomycin A was further conducted and the antibacterial activity was determined. This study provides a guide for the rational design of analogues based on uridylpeptide antibiotics.

show abstract

“…5,6 Unlike some other proteasome inhibitors, even some used clinically, the syrbactin syringolin A (SylA) is quite selective for proteasome β subunits over other protein targets, as demonstrated by affinity-based protein profiling. 7–9 Several syntheses of the natural syrbactins themselves have been reported, and significant work to prepare analogs has been pursued. 10–13 We recently reported the compound TIR-199 (Chart 1), 14 the first syrbactin to demonstrate activity against tumor cell lines in animal studies.…”

Section: Introductionmentioning

confidence: 99%

Immunoproteasome inhibition and bioactivity of thiasyrbactins

Bakas

Schultz

Yco

et al. 2018

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

A family of macrodilactam natural products, the syrbactins, are known proteasome inhibitors. A small group of syrbactin analogs was prepared with a sulfur-for-carbon substitution to enhance synthetic accessibility and facilitate modulation of their solubility. Two of these compounds surprisingly proved to be inhibitors of the trypsin-like catalytic site, including of the immunoproteasome. Their bound and free conformations suggest special properties of the thiasyrbactin ring are responsible for this unusual preference, which may be exploited to develop drug-like immunoproteasome inhibitors. These compounds show greater selectivity than earlier compounds used to infer phenotypes of immunoproteasome inhibition, like ONX-0914.

show abstract

Total Synthesis of Syringolin A and Improvement of Its Biological Activity

Cited by 7 publications

References 23 publications

Syrbactin Structural Analog TIR-199 Blocks Proteasome Activity and Induces Tumor Cell Death

Syrbactin Structural Analog TIR-199 Blocks Proteasome Activity and Induces Tumor Cell Death

Elucidating the Structural Requirement of Uridylpeptide Antibiotics for Antibacterial Activity

Immunoproteasome inhibition and bioactivity of thiasyrbactins

Contact Info

Product

Resources

About