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dc.contributor.authorDunsmore, Lavinia
dc.contributor.authorNavo, Claudio D
dc.contributor.authorBecher, Julie
dc.contributor.authorde Montes, Enrique Gil
dc.contributor.authorGuerreiro, Ana
dc.contributor.authorHoyt, Emily
dc.contributor.authorBrown, Libby
dc.contributor.authorZelenay, Viviane
dc.contributor.authorMikutis, Sigitas
dc.contributor.authorCooper, Jonathan
dc.contributor.authorBarbieri, Isaia
dc.contributor.authorLawrinowitz, Stefanie
dc.contributor.authorSiouve, Elise
dc.contributor.authorMartin, Esther
dc.contributor.authorRuivo, Pedro R
dc.contributor.authorRodrigues, Tiago
dc.contributor.authorda Cruz, Filipa P
dc.contributor.authorWerz, Oliver
dc.contributor.authorVassiliou, George
dc.contributor.authorRavn, Peter
dc.contributor.authorJiménez-Osés, Gonzalo
dc.contributor.authorLopes Bernardes, Goncalo
dc.date.accessioned2022-07-05T15:01:13Z
dc.date.available2022-07-05T15:01:13Z
dc.date.issued2022-07
dc.date.submitted2021-02-04
dc.identifier.issn1755-4330
dc.identifier.others41557-022-00964-7
dc.identifier.other964
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338786
dc.description.abstractNatural 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.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectArticle
dc.subject/639/638/92/152
dc.subject/631/67/1059/602
dc.subject/639/638/309/2144
dc.subjectarticle
dc.titleControlled masking and targeted release of redox-cycling ortho-quinones via a C-C bond-cleaving 1,6-elimination.
dc.typeArticle
dc.date.updated2022-07-05T15:01:11Z
prism.endingPage765
prism.issueIdentifier7
prism.publicationNameNat Chem
prism.startingPage754
prism.volume14
dc.identifier.doi10.17863/CAM.86193
dcterms.dateAccepted2022-05-03
rioxxterms.versionofrecord10.1038/s41557-022-00964-7
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidDunsmore, Lavinia [0000-0002-9125-6081]
dc.contributor.orcidNavo, Claudio D [0000-0003-0161-412X]
dc.contributor.orcidBecher, Julie [0000-0002-8417-4475]
dc.contributor.orcidHoyt, Emily [0000-0001-6940-8803]
dc.contributor.orcidMikutis, Sigitas [0000-0003-0064-639X]
dc.contributor.orcidBarbieri, Isaia [0000-0003-3035-8970]
dc.contributor.orcidWerz, Oliver [0000-0002-5064-4379]
dc.contributor.orcidVassiliou, George [0000-0003-4337-8022]
dc.contributor.orcidJiménez-Osés, Gonzalo [0000-0003-0105-4337]
dc.contributor.orcidLopes Bernardes, Goncalo [0000-0001-6594-8917]
dc.identifier.eissn1755-4349
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Marie Sklodowska-Curie actions (792495)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (1795534)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/M011194/1)
pubs.funder-project-idCancer Research UK (A25117)
pubs.funder-project-idEuropean Research Council (812994)
pubs.funder-project-idEuropean Commission (EC) (852985)
cam.issuedOnline2022-06-27


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