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Publication
Bio-triggered triazenes : a novel approach to release alkylating agents
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Authors
Abstract(s)
Glioblastoma multiforme (GBM) is the most prevalent and invasive type of glioma, and patients present a median survival time of only 14 months after diagnosis. Temozolomide (TMZ) is a triazene-based prodrug approved for the treatment of high-grade brain tumours such as GBM, however, the highly heterogeneous and wide-spreading nature of glioma cells often disrupts its efficacy, resulting in resistance to chemotherapy, lack of selectivity for cancer cells and high tumour recurrence. Similarly to TMZ, 1-aryl-3-methyltriazenes are alkylating agents that have been developed in prodrug forms for targeted drug delivery, with reported anti-tumoral activities in the micromolar range against melanoma and glioblastoma cell lines.
In this work, we aimed to target hypoxia which represents a key feature of GBM microenvironment with a set of nitroaromatic-based triazene prodrugs 14a-f, 22a-f and 47a-c designed to be selectively activated under hypoxia to release the cytotoxic methyldiazonium ion. The incorporation of different nitroaromatic triggers translated into variable rates of reduction towards E. coli nitroreductase NfsB. Biological evaluation under normoxic and hypoxic cultures of LN-229 and U-87MG glioblastoma cell lines revealed that compounds 14b, 14d and 14e exhibited a more pronounced cytotoxic effect than the same dose of TMZ, with minimal toxicity against normal primary fibroblast cells. Moreover, cell death by apoptosis and ROS production revealed to be increased in the presence of the selected prodrugs.
Furthermore, we designed a dual function chromenone-based fluorescent probe to be activated under hypoxia, using NOBF4 for adequate diazonium salt stabilization before monomethyltriazene formation. However, the synthetic route still requires optimization and further examination on the apparent instability of the final dual-function molecule.
Finally, hybrid compounds based on valproic acid and DNA-alkylating triazene moieties previously designed for GBM chemotherapy, were evaluated in GL261 cell line and compounds 67d and 67e shown to be remarkably more potent against glioma cells and more efficient in decreasing invasive cell properties than TMZ. In contrast to TMZ, which undergoes hydrolysis to release an alkylating metabolite, the valproate hybrids showed a low potential to alkylate DNA.
This work contributed with two new categories of triazene prodrugs with confirmed in vitro anti-cancer activity. Altogether, these data validate the feasibility of the incorporation of triazenes in targeted-drug delivery platforms specifically designed to target glioblastoma multiforme.
Description
Keywords
1-aril-3-metiltriazenos agentes alquilantes glioblastoma multiforme hipóxia sistema de entrega direcionada de fármacos 1-aryl-3-methyltriazenes alkylating agents glioblastoma multiforme hypoxia targeted-drug delivery system