Discovery of novel NO-releasing celastrol derivatives with Hsp90 inhibition and cytotoxic activities

Eur J Med Chem. 2018 Dec 5:160:1-8. doi: 10.1016/j.ejmech.2018.10.013. Epub 2018 Oct 6.

Abstract

To develop multifunctional drugs, a series of celastrol/NO donor hybrids were designed, synthesized and evaluated. The detection of NO release amounts showed that the more NO of these hybrids released, the more tumor cells were inhibited. 11b, which released the highest level of NO in vitro, exhibited superior potency (IC50 = 0.48 ± 0.06 μM) compared to the other compounds. Further pharmacological studies showed that 11b induced dysregulations of the Hsp90 clients (Akt and Cdk4), apoptosis, and cell cycle arrested at G0/G1 phase against A549 cells. These results suggested that inhibition of Hsp90 and release of NO was synergistic in cancer cells. Overall, the NO-releasing capacity and the inhibition of Hsp90 pathway signaling might explain the potent anti-proliferative activities of these compounds.

Keywords: Apoptosis; Celastrol; Cytotoxicity; Hsp 90; Nitric oxide.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Molecular Structure
  • Nitric Oxide / chemistry*
  • Nitric Oxide / metabolism
  • Pentacyclic Triterpenes
  • Structure-Activity Relationship
  • Triterpenes / chemistry
  • Triterpenes / metabolism
  • Triterpenes / pharmacology*

Substances

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Pentacyclic Triterpenes
  • Triterpenes
  • Nitric Oxide
  • celastrol