Syntheses and cytotoxicity of syringolin B-based proteasome inhibitors

Ibarra‐Rivera, Tannya R.; Opoku-Ansah, John; Sudhakar, Ambadi; Bachmann, André S.; Pirrung, Michael C.

doi:10.1016/j.tet.2011.09.048

Cited by 15 publications

(17 citation statements)

References 29 publications

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“…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.…”

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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

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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.

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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

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“…13 The free base was then coupled with a valine active ester to provide 13 . (60%) Removal of its Fmoc group and urea formation with dodecyl isocyanate provided the first target 1 .…”

Section: Resultsmentioning

confidence: 99%

“…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. It is most potent against the chymotrypsin-like activity of the β5 constitutive proteasome subunit, which can be ascribed to structural features derived from other syrbactins including the natural product glidobactin A, which was discovered through its intrinsic activity against tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Immunoproteasome inhibition and bioactivity of thiasyrbactins

Bakas

Schultz

Yco

et al. 2018

Bioorganic & Medicinal Chemistry

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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.

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“…Most recently, the structural analogue TIR-203 was synthesized by the UC Riverside group, inspired by the structural properties of syringolin B (Ibarra-Rivera et al, 2011). Syringolin B is a favored platform for the design of structural variants because a large portion of its structure is based on lysine, analogues of which can be readily accessed.…”

Section: Research Articlementioning

confidence: 99%