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  3. Targeting gliomas with triazene-based hybrids: Structure-activity relationship, mechanistic study and stability

Targeting gliomas with triazene-based hybrids: Structure-activity relationship, mechanistic study and stability

  • Eur J Med Chem. 2019 Jun 15:172:16-25. doi: 10.1016/j.ejmech.2019.03.048.
Cláudia Braga 1,  Ana R Vaz 1,  M Conceição Oliveira 2,  M Matilde Marques 2,  Rui Moreira 1,  Dora Brites 1,  Maria J Perry 3
Affiliations

Affiliations

  • 1 Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal.
  • 2 Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
  • 3 Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address: mjprocha@ff.ulisboa.pt.
PMID: 30939350 DOI: 10.1016/j.ejmech.2019.03.048
Abstract

Herein we report novel hybrid compounds based on valproic acid and DNA-alkylating triazene moieties, 1, with therapeutic potential for glioblastoma multiforme chemotherapy. We identified hybrid compounds 1d and 1e to be remarkably more potent against glioma and more efficient in decreasing invasive cell properties than temozolomide and endowed with chemical and plasma stability. In contrast to temozolomide, which undergoes hydrolysis to release an alkylating metabolite, the valproate hybrids showed a low potential to alkylate DNA. Key physicochemical properties align for optimal CNS penetration, highlighting the potential of these effective triazene based-hybrids for enhanced Anticancer chemotherapy.

Keywords

Histone deacetylase inhibitors; Multi-targeted glioma therapy; Triazenes; Valproic acid.

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