Controlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.
Authors
de Montes, Enrique Gil
Guerreiro, Ana
Brown, Libby
Zelenay, Viviane
Cooper, Jonathan
Lawrinowitz, Stefanie
Siouve, Elise
Martin, Esther
Ruivo, Pedro R
Rodrigues, Tiago
da Cruz, Filipa P
Ravn, Peter
Publication Date
2022-07Journal Title
Nat Chem
ISSN
1755-4330
Publisher
Springer Science and Business Media LLC
Volume
14
Issue
7
Pages
754-765
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Dunsmore, L., Navo, C. D., Becher, J., de Montes, E. G., Guerreiro, A., Hoyt, E., Brown, L., et al. (2022). Controlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.. Nat Chem, 14 (7), 754-765. https://doi.org/10.1038/s41557-022-00964-7
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.
Keywords
Article, /639/638/92/152, /631/67/1059/602, /639/638/309/2144, article
Sponsorship
European Commission Horizon 2020 (H2020) Marie Sklodowska-Curie actions (792495)
Biotechnology and Biological Sciences Research Council (1795534)
Biotechnology and Biological Sciences Research Council (BB/M011194/1)
Cancer Research UK (A25117)
European Research Council (812994)
European Commission (EC) (852985)
Identifiers
s41557-022-00964-7, 964
External DOI: https://doi.org/10.1038/s41557-022-00964-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338786
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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