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

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 ringopened 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.

Tf2O-Promoted Morgan–Walls Reaction: From a Flexible Approach to Functionalized Phenanthridines and Quinazolines to the Short and Divergent Total Syntheses of Alkaloids

“…3 In addition, the phenanthridine motif is found in a number of alkaloids (e.g., 4 – 10 ; Figure 1 ) that show a broad spectrum of bioactivities. 4 For example, trisphaeridine 5 (trispheridine, 4 ), 5,6-dihydrobicolorine 5e 6 ( 6 ), bicolorine 5b 6a ( 7 ), N -methylcrinasiadine 5b d ( 8 ), zephycandidine A 7 ( 9 ), and sanguinarine 8a ( 10 ) exhibit antitumor, 5c h 8 antipolioviral, neuroprotective, 5e antimigratory, strong acetylcholinesterase (AChE) inhibitory, 5e 7 and Bcl-X L inhibitory activities. 8b Moreover, phenanthridine derivatives serve, on one hand, as versatile building blocks for the synthesis of functional materials, 9 and on the other hand, as a new kind of chiral NAD(P)H model.…”

“…12b More recently, a method for the in-cell generation of anticancer 6-alkylphenanthridine derivatives through bioorthogonal cyclization of antitumor prodrugs has been disclosed. 5h The aforementioned achievements highlight, on one hand, the high potential of phenanthridine derivatives for medicinal applications, and on the other hand, the need to develop mild and versatile methods for their synthesis.…”