期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 45, 页码 24043-24047出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202110041
关键词
Antitumor agents; bioorthogonal chemistry; phenanthridine; prodrug; reactive oxygen species
资金
- Ministere de l'Education Nationale de la Recherche et de la Technologie
- Fondation ARC pour la recherche sur le cancer
A new platform capable of generating cytotoxic agents through intramolecular cyclization has been reported, showing rapid and effective action against cancer cells. This innovative method offers potential for prodrug development in anticancer therapy.
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. Here, we report a platform able to generate the cytotoxic agent by intramolecular cyclization. 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 inside living cells of KB cancer spheroids so as to circumvent drug action.
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