2. Academic Validation
  3. Streptogramin A derivatives as mitochondrial translation inhibitors to suppress glioblastoma stem cell growth

Streptogramin A derivatives as mitochondrial translation inhibitors to suppress glioblastoma stem cell growth

  • Eur J Med Chem. 2023 Jan 15;246:114979. doi: 10.1016/j.ejmech.2022.114979.
Denise Sighel 1,  Giulia Battistini 2,  Emanuele Filiberto Rosatti 3,  Jacopo Vigna 2,  Matteo Pavan 4,  Romina Belli 5,  Daniele Peroni 5,  Federica Alessandrini 3,  Sara Longhi 3,  Michael Pancher 6,  Joanna Rorbach 7,  Stefano Moro 4,  Alessandro Quattrone 3,  Ines Mancini 8
Affiliations

Affiliations

  • 1 Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123, Povo, Trento, Italy. Electronic address: [email protected].
  • 2 Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123, Povo, Trento, Italy.
  • 3 Laboratory of Translational Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123, Povo, Trento, Italy.
  • 4 Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131, Padova, Italy.
  • 5 Mass Spectrometry and Proteomics Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123, Povo, Trento, Italy.
  • 6 High Throughput Screening (HTS) and Validation Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123, Povo, Trento, Italy.
  • 7 Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Biomedicum, Solnavägen 9, 171 65, Solna, Stockholm, Sweden.
  • 8 Laboratory of Bioorganic Chemistry, Department of Physics, University of Trento, Via Sommarive 14, 38123, Povo, Trento, Italy. Electronic address: [email protected].
PMID: 36495628 DOI: 10.1016/j.ejmech.2022.114979
Abstract

New therapeutic strategies for glioblastoma treatment, especially tackling the tumour's glioblastoma stem cell (GSC) component, are an urgent medical need. Recently, mitochondrial translation inhibition has been shown to affect GSC growth, clonogenicity, and self-renewal capability, therefore becoming an attractive therapeutic target. The combination of streptogramins B and A Antibiotics quinupristin/dalfopristin (Q/D), which inhibits mitochondrial ribosome function, affects GSCs more effectively in vitro than the standard of care temozolomide. Here, docking calculations based on the cryo-EM structure of the Q/D-bound mitochondrial ribosome have been used to develop a series of streptogramin A derivatives. We obtained twenty-two new and known molecules starting from the dalfopristin and virginiamycin M1 scaffolds. A structure-activity relationship refinement was performed to evaluate the capability of these compounds to suppress GSC growth and inhibit mitochondrial translation, either alone or in combination with quinupristin. Finally, quantitative ultra HPLC-mass spectrometry allowed us to assess the cell penetration of some of these derivatives. Among all, the fluorine derivatives of dalfopristin and virginiamycin M1, (16R)-1e and (16R)-2e, respectively, and flopristin resulted in being more potent than the corresponding lead compounds and penetrating to a greater extent into the cells. We, therefore, propose these three compounds for further evaluation in vivo as antineoplastic agents.

Keywords

Anticancer drugs; Dalfopristin/quinupristin; Glioblastoma stem cells; Mitochondrial ribosome inhibition; Molecular docking; Streptogramin A derivatives.

Figures
Products