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In‐Cell Generation of Anticancer Phenanthridine Through Bioorthogonal Cyclization in Antitumor Prodrug Development

2 nov. 2021Angewandte Chemie International Edition

DOI : 10.1002/anie.202110041

Auteurs

Hichem Maslah, Charles Skarbek, Catherine Gourson, Marie‐Aude Plamont, Stéphanie Pethe, Ludovic Jullien, Thomas Le Saux, Raphaël Labruère

Résumé

Abstract

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.

Membres

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RAPHAEL LABRUERE

Maître de conférences Université Paris Saclay