2. Academic Validation
  3. Chemical modifications of imidazole-containing alkoxyamines increase C-ON bond homolysis rate: Effects on their cytotoxic properties in glioblastoma cells

Chemical modifications of imidazole-containing alkoxyamines increase C-ON bond homolysis rate: Effects on their cytotoxic properties in glioblastoma cells

  • Bioorg Med Chem. 2019 May 15;27(10):1942-1951. doi: 10.1016/j.bmc.2019.03.029.
Toshihide Yamasaki 1,  Duje Buric 2,  Christine Chacon 2,  Gérard Audran 1,  Diane Braguer 3,  Sylvain R A Marque 4,  Manon Carré 5,  Paul Brémond 6
Affiliations

Affiliations

  • 1 Aix Marseille Univ, CNRS, ICR, Marseille, France.
  • 2 Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France.
  • 3 Aix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, Marseille, France; APHM, Hôpital Timone, Marseille, France.
  • 4 Aix Marseille Univ, CNRS, ICR, Marseille, France; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Lavrentieva 9, Novosibirsk 630090, Russian Federation.
  • 5 Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: manon.carre@univ-amu.fr.
  • 6 Aix Marseille Univ, CNRS, ICR, Marseille, France; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: paul.bremond@univ-amu.fr.
PMID: 30975504 DOI: 10.1016/j.bmc.2019.03.029
Abstract

Previously, we described alkoxyamines bearing a pyridine ring as new pro-drugs with low molecular weights and theranostic activity. Upon chemical stimulus, alkoxyamines undergo homolysis and release free radicals, which can, reportedly, enhance magnetic resonance imaging and trigger Cancer cell death. In the present study, we describe the synthesis and the anti-cancer activity of sixteen novel alkoxyamines that contain an imidazole ring. Activation of the homolysis was conducted by protonation and/or methylation. These new molecules displayed cytotoxic activities towards human glioblastoma cell lines, including the U251-MG cells that are highly resistant to the conventional chemotherapeutic agent Temozolomide. We further showed that the biological activities of the alkoxyamines were not only related to their half-life times of homolysis. We lastly identified the alkoxyamine (RS/SR)-4a, with both a high antitumour activity and favourable logD7.4 and pKa values, which make it a robust candidate for blood-brain barrier penetrating therapeutics against brain neoplasia.

Keywords

Alkoxyamines; Alkyl radicals; Antitumour activity; Glioblastoma.

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