Nitroaromatic-based triazene prodrugs to target the hypoxic microenvironment in glioblastoma.

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RSC medicinal chemistry Pub Date : 2025-01-20 DOI:10.1039/d4md00876f
Cláudia Braga, Margarida Ferreira-Silva, M Luísa Corvo, Rui Moreira, Alexandra R Fernandes, João Vaz, Maria J Perry
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Abstract

Hypoxia is a hallmark of the glioblastoma multiforme microenvironment and represents a promising therapeutic target for cancer treatment. Herein, we report nitroaromatic-based triazene prodrugs designed for selective activation by tumoral endogenous reductases and release of the cytotoxic methyldiazonium ion via a self-immolative mechanism. While compounds bearing a 2-nitrofuran bioreductive group were more efficiently activated by nitroreductases, 4-nitrobenzyl prodrugs 1b, 1d and 1e elicited a more pronounced cytotoxic effect against LN-229 and U-87 MG glioblastoma cell lines under hypoxic conditions when compared to temozolomide (TMZ), the golden standard for glioblastoma treatment. This cytotoxic response aligns with the increased apoptosis levels in LN-229 cells and senescence induction in U-87 MG cells, promoted by prodrugs 1d and 1e, under hypoxic conditions. These results highlight the potential of these hypoxia-activated nitroaromatic-based triazene prodrugs for selective delivery of the cytotoxic methyldiazonium ion and support further optimization to provide a safer alternative for glioblastoma treatment.

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5.80
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2.40%
发文量
129
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