In‐Cell Generation of Anticancer Phenanthridine Through Bioorthogonal Cyclization in Antitumor Prodrug Development
| Autor: | Charles Skarbek, Hichem Maslah, Marie-Aude Plamont, Stéphanie Pethe, Catherine Gourson, Thomas Le Saux, Ludovic Jullien, Raphaël Labruère |
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| Rok vydání: | 2021 |
| Předmět: |
Phenanthridine
Molecular Structure Chemistry Cell Survival Biological activity Antineoplastic Agents General Chemistry Drug action General Medicine Prodrug Combinatorial chemistry Catalysis KB Cells Phenanthridines chemistry.chemical_compound Drug Development Cyclization Cancer cell Cytotoxic T cell Humans Prodrugs Bioorthogonal chemistry Drug Screening Assays Antitumor Cytotoxicity Cell Proliferation |
| Zdroj: | Angewandte Chemie. 133:24245-24249 |
| ISSN: | 1521-3757 0044-8249 |
| Popis: | Pharmacological inactivation of antitumor drugs toward healthy cells is a critical factor in prodrug development. Typically, pharmaceutical chemists graft temporary moieties to existing antitumor drugs to reduce their pharmacological activity as much as possible. Here, we report a platform where the structure of the prodrug excludes the preexisting antitumor drug motif and is based on an inactive synthetic precursor able to generate the cytotoxic agent by bioorthogonal cyclization within a tumor environment. Using phenanthridines as cytotoxic model compounds, we designed ring-opened biaryl precursors that generated the phenanthridines through bioorthogonal irreversible imination. This reaction was triggered by reactive oxygen species, commonly overproduced in cancer cells, able to convert a vinyl boronate ester function into a ketone that subsequently reacted with a pendant aniline. An inactive precursor was shown to engender a cytotoxic phenanthridine against KB cancer cells. Moreover, the kinetic of cyclization of this prodrug was extremely rapid (˂ 10 ms) inside living cells of KB cancer spheroids so as to circumvent drug action. |
| Databáze: | OpenAIRE |
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