Examination of sulfonamide-based inhibitors of MMP3 using the conditioned media of invasive glioma cells

J Enzyme Inhib Med Chem. 2020 Dec;35(1):672-681. doi: 10.1080/14756366.2020.1715387.

Abstract

Glioblastoma multiforme (GBM) is the deadliest and the most common primary malignant brain tumour. The median survival for patients with GBM is around one year due to the nature of glioma cells to diffusely invade that make the complete surgical resection of tumours difficult. Based upon the connexin43 (Cx43) model of glioma migration we have developed a computational framework to evaluate MMP inhibition in materials relevant to GBM. Using the ilomastat Leu-Trp backbone, we have synthesised novel sulphonamides and monitored the performance of these compounds in conditioned media expressing MMP3. From the results discussed herein we demonstrate the performance of sulfonamide based MMPIs included AP-3, AP-6, and AP-7.

Keywords: Matrix metalloproteinase; glioblastoma multiforme; ilomastat; inhibition.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Matrix Metalloproteinase 3 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Matrix Metalloproteinase Inhibitors
  • Sulfonamides
  • MMP3 protein, human
  • Matrix Metalloproteinase 3

Grants and funding

EACB and VCC thank NSERC for funding. VCC also thanks the Brandon University Research Committee (BURC), the Brandon University Faculty of Science and the Canadian Foundation for Innovation (CFI). CN was supported by the Canadian Research Chairs (CRC) Program and the Canadian Institute for Health Research (CIHR). ATP was supported by a Fredrick Banting and Charles Best Canada Graduate Scholarship (CGSM). CL was supported by a Bruce and Jane Forest Memorial Scholarship. EACB and CAS thank ComputeCanada for computational resources.