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

Abstract

Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (CÀ C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of β-lapachone (β-lap), an ortho-quinone natural product without traditional modifiable groups for the construction of CÀ N/CÀ O bond cleavage-based prodrugs. The designed β-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing β-lap. It exerted anticancer efficacy via NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling, resulting in potent cytotoxicity that was highly selective for NQO1rich cancer cells over normal cells both in vitro and in vivo. This significantly amplified the therapeutic window of β-lap. This study provides a practical strategy for the design of prodrugs for parent drugs that do not contain traditional modifiable groups.

A Quantum Computing Pipeline for Real World Drug Discovery: From Algorithm to Quantum Hardware

“…In this work, we study the prodrug design for β -lapachone, a natural product with extensive anticancer activity. In the original study [14], the authors use DFT and select M06-2X functional to calculate the energy barrier. The results show that the energy barrier for C-C bond cleavage is small enough for the chemical reaction to proceed spontaneously under physiological temperature conditions.…”

“…Among various prodrug activation strategies [14][15][16][17][18][19][20][21], that based on the cleavage of carboncarbon (C-C) bonds is particularly innovative. It is a novel strategy with applicability to drugs without traditional modifiable groups.…”

“…Our first case study focuses on a carbon-carbon bond cleavage prodrug strategy[14], which investigates an innovative prodrug activation approach applied to β -lapachone for cancer-specific targeting and has been validated through animal experiments. This prodrug design primarily aims to address the limitations of active drugs in pharmacokinetics and pharmacodynamics, offering a valuable supplement to the existing prodrug strategies[15–21].…”

Multifunctional Fe-based coordination polymer nano-bomb modified with β-lapachone and CaO2 for targeted tumor dual chemodynamic therapy with enhanced ferroptosis and H2O2 self-supply

“…Accordingly, transplantation of H 2 O 2 -affording agents in CDT platforms is a frequent strategy to enhance its antitumor effect. Typically, glucose oxidase or β-lapachone (β-lap) could increase endogenous H 2 O 2 dose via mediating or involving the catalytic reactions with substrates (e.g., glucose) or enzymes (e.g., nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase-1, NQO1) in the tumor microenvironment [ 14 , 15 ], which are used as the natural donors of H 2 O 2 and potential enhancer of CDT. Nevertheless, almost all of these catalytic reactions need O 2 to participate directly or indirectly, and the actual hypoxia and continuous depletion of O 2 further impedes CDT effect [ 16 ].…”

Multifunctional nano-bomb based on Fe-COF for targeted tumor dual chemodynamic therapy and bioimaging with enhanced ferroptosis and H2O2 self-supply

“…Accordingly, transplantation of H 2 O 2 -affording agents in CDT platforms is a frequent strategy to enhance its antitumor effect. Typically, glucose oxidase or β-lapachone (β-lap) could increase endogenous H 2 O 2 dose via mediating or involving the catalytic reactions with substrates (e.g., glucose) or enzymes (e.g., nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase-1, NQO1) in the tumor microenvironment [14,15], which are used as the natural donors of H 2 O 2 and potential enhancer of CDT. Nevertheless, almost all of these catalytic reactions need O 2 to participate directly or indirectly, and the actual hypoxia and continuous depletion of O 2 limits the su cient supplement of H 2 O 2 and impedes CDT effect [16].…”