ArticleNature chemistry2022
Controlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.
Article in Nature chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 38 citations in OpenAlex.
- Article
- Antiviral drug discovery and development: challenges and future directions.Signal transduction and targeted therapy · 2026Review
- Expanding the payload scope in antibody-drug conjugates by delivery of hydroxy-containing drugs through self-immolative phosphoramidates.Nature communications · 2026Article
- Controlled Self-Immolative Release of β-Lapachone via an OptimizedJournal of the American Chemical Society · 2025Article
- Trihydroxybenzaldoximes are Redox Cycling Inhibitors of ThDP-Dependent DXP Synthase.ACS chemical biology · 2025Article
- Insights into the Sources, Structure, and Action Mechanisms of Quinones on Diabetes: A Review.Molecules (Basel, Switzerland) · 2025Review
- Prodrug activation by 4,4'-bipyridine-mediated aromatic nitro reduction.Nature communications · 2024Article
- A novel bioresponsive self-immolative spacer based on aza-quinone methide reactivity for the controlled release of thiols, phenols, amines, sulfonamides or amides.Chemical science · 2024Article
- Machine Learning Uncovers Natural Product Modulators of the 5-Lipoxygenase Pathway and Facilitates the Elucidation of Their Biological Mechanisms.ACS chemical biology · 2024Article
- Photophysical properties of four-membered BNJournal of molecular modeling · 2023Article
- Review
- β-lapachone regulates mammalian inositol pyrophosphate levels in an NQO1- and oxygen-dependent manner.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Expanding Transition Metal-Mediated Bioorthogonal Decaging to Include C-C Bond Cleavage Reactions.Journal of the American Chemical Society · 2023Article
- α-Mangostin Promotes In Vitro and In Vivo Degradation of Androgen Receptor and AR-V7 Splice Variant in Prostate Cancer Cells.Cancers · 2023Article
- Sulfamate Acetamides as Self-Immolative Electrophiles for Covalent Ligand-Directed Release Chemistry.Journal of the American Chemical Society · 2023Article
- Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development.Cancers · 2022Review
- ortho-Quinone drugs go pro.Nature chemistry · 2022Article
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22 authors at 7 institutions in 5 countries.
Funding
Abstract
Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol. Upon a specific enzymatic trigger, an acid-promoted, self-immolative C-C bond-cleaving 1,6-elimination mechanism releases the redox-active hydroquinone inside cells. By using a 5-lipoxygenase modulator, β-lapachone, we created cathepsin-B-cleavable quinone prodrugs. We applied the strategy for intracellular release of β-lapachone upon antibody-mediated delivery. Conjugation of protected β-lapachone to Gem-IgG1 antibodies, which contain the variable region of gemtuzumab, results in homogeneous, systemically non-toxic and conditionally stable CD33+-specific antibody-drug conjugates with in vivo efficacy against a xenograft murine model of acute myeloid leukaemia. This protection strategy could allow the use of previously overlooked natural products as anticancer agents, thus extending the range of drugs available for next-generation targeted therapeutics.
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