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.

A Stimuli‐Responsive Small‐Molecule Metal‐Carrying Prochelator: A Novel Prodrug Design Strategy for Metal Complexes

“…[27] We designed and synthesized two kinds of prodrugs by integrating DTC and DPA (named DPBD and DPPBD, respectively) via the H 2 O 2 -triggered cleavable phenylborate ester bond, [1b, 28] which may undergo 1,6-elimination or 1,4-elimination to release DTC in the presence of H 2 O 2 . The synthesis routes of the prodrugs DPBD and DPPBD are shown in Scheme S1 and Scheme S2, respectively, and the corresponding chemical structures were characterized by 1 H NMR, 13 C NMR, 1 H-1 H COSY NMR, HSQC NMR, HMBC NMR, ESI-MS and HPLC (Figure S10-S39).…”

“…In addition, DPD without phenylborate ester bond was synthesized as the negative control. The synthesis route of DPD is shown in Scheme S3 and the corresponding chemical structures were characterized by 1 H NMR, 13 C NMR, 1 H-1 H COSY NMR, HSQC NMR, HMBC NMR, ESI-MS and HPLC (Figure S40-S46).…”

“…[12] The main advantage of this synthetic prodrug strategy is the significant difference in bioactivity because of the radically different structures of the prodrug and the active drug, which can greatly improve drug selectivity and reduce side effects. [13] In most cases, prodrug and another compound are simultaneously needed as bioorthogonal reaction pair for activation. [14] Thus, two independent administrations are usually carried out.…”

“…This means that prodrugs can be activated via in situ synthesis of bioactive drugs by a rational bioorthogonal reaction, such as the common copper(I)‐catalyzed azide–alkyne cycloaddition, [10] cyclization (for phenanthridinium derivatives), [11] and ring closing metathesis (for phenyl moiety) [12] . The main advantage of this synthetic prodrug strategy is the significant difference in bioactivity because of the radically different structures of the prodrug and the active drug, which can greatly improve drug selectivity and reduce side effects [13] . In most cases, prodrug and another compound are simultaneously needed as bioorthogonal reaction pair for activation [14] .…”

A Carbon‐Carbon Bond Cleavage‐Based Prodrug Activation Strategy Applied to β‐Lapachone for Cancer‐Specific Targeting

“…With the optimal conditions in hand, the substrate scope, including various ortho-quinones and benzylbromides, was investigated (Figure 3B). In addition to 1, this reaction proved to work for ortho-quinones such as 9,10-phenanthroquinone (10), tanshinone IIA (11) and its ortho-quinone analogue 12, and nor-β-lapachone (13) to generate C-benzyl derivatives 14-21. These results demonstrated well compatibility of the reaction with ortho-quinones to generate CÀ C coupling…”