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

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. [Display omitted] •Multitarget approach for glioma treatment combining aryltriazenes and HDAC inhibitors.•Key physicochemical properties suitable to ensure BBB penetration.•Enhanced and selective cytotoxic action on glioma cell lines compared to the drug Temozolomide.•Triazene-based hybrids improved cytotoxicity is unrelated to DNA alkylation.