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  3. Enhanced tumor specific drug release by hypoxia sensitive dual-prodrugs based on 2-nitroimidazole

Enhanced tumor specific drug release by hypoxia sensitive dual-prodrugs based on 2-nitroimidazole

  • Bioorg Med Chem Lett. 2023 Oct 15:95:129484. doi: 10.1016/j.bmcl.2023.129484.
Takashi Tsuji 1,  Honoka Tsunematsu 1,  Masaki Imanishi 1,  Masaya Denda 1,  Koichiro Tsuchiya 1,  Akira Otaka 2
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, Japan.
  • 2 Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, Japan. Electronic address: [email protected].
PMID: 37716415 DOI: 10.1016/j.bmcl.2023.129484
Abstract

Hypoxia in Cancer is important in the development of cancer-selective medicines. Here, a novel hypoxia-responsible dual-prodrug is described. We designed and synthesized 2-nitroimidazole derivatives which spontaneously release both a PYG inhibitor and gemcitabine under hypoxic conditions. One such derivative, a prodrug 9 was found to be stable against chemical and enzymatic hydrolysis, and upon chemical reduction of the nitro group on imidazole, successfully releases both drugs. In an in vitro proliferation assay using human pancreatic cells, compound 9 exhibited significant anti-proliferative effects in hypoxia but fewer effects in normoxia. Consequently, prodrug 9 should be useful for Cancer treatment due to its improved Cancer selectivity and potential to overcome drug resistance.

Keywords

Gemcitabine; Hypoxia; Nitroimidazole; Prodrug.

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