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

• Published in: Bioorganic & medicinal chemistry 2019-05, Vol.27 (10), p.1942-1951
• Main Authors: Yamasaki, Toshihide, Buric, Duje, Chacon, Christine, Audran, Gérard, Braguer, Diane, Marque, Sylvain R.A., Carré, Manon, Brémond, Paul
• Format: Article
• Language: English
• Subjects: Alkoxyamines; Alkyl radicals; Amines - chemistry; Amines - metabolism; Amines - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antitumour activity; Carbon - chemistry; Cell Line, Tumor; Cell Survival - drug effects; Chemical Sciences; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; Half-Life; Humans; Imidazoles - chemistry; Nitrogen - chemistry; Oxygen - chemistry; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacology; Stereoisomerism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.03.029

[Display omitted] •Imidazole-containing alkoxyamines are alkyl radical-releasing compounds.•Homolysis of alkoxyamines can be triggered by methylation and/or protonation.•Half-life time of homolysis, pKa and logD7.4 modulate their biological activity.•Alkoxyamines are cytotoxic in drug-sensitive and drug-resistant glioblastoma cells.•Alkoxyamine (RS/SR)-4a showed the highest in vitro antitumour activity. 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.