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dc.contributor.authorOrtuzar, N.
dc.contributor.authorKaru, K.
dc.contributor.authorPresa, Daniela
dc.contributor.authorMorais, Goreti R.
dc.contributor.authorSheldrake, Helen M.
dc.contributor.authorShnyder, Steve D.
dc.contributor.authorBarnieh, Francis M.
dc.contributor.authorLoadman, Paul M.
dc.contributor.authorPatterson, Laurence H.
dc.contributor.authorPors, Klaus
dc.contributor.authorSearcey, M.
dc.date.accessioned2021-07-06T12:25:32Z
dc.date.accessioned2021-07-22T08:02:45Z
dc.date.available2021-07-06T12:25:32Z
dc.date.available2021-07-22T08:02:45Z
dc.date.issued2021-06-15
dc.identifier.citationOrtuzar N, Karu K, Presa D et al (2021) Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds. Bioorganic and Medicinal Chemistry. 40: 116167.en_US
dc.identifier.urihttp://hdl.handle.net/10454/18559
dc.descriptionYesen_US
dc.description.abstractThe duocarmycins belong to a class of agent which has great potential for use in cancer therapy. Their exquisite potency means they are too toxic for systemic use, and targeted approaches are required to unlock their clinical potential. In this study, we have explored seco-OH-chloromethylindoline (CI) duocarmycin-based bioprecursors for their potential for cytochrome P450 (CYP)-mediated cancer cell kill. We report on synthetic and biological explorations of racemic seco-CI-MI, where MI is a 5-methoxy indole motif, and dehydroxylated analogues. We show up to a 10-fold bioactivation of de-OH CI-MI and a fluoro bioprecursor analogue in CYP1A1-transfected cells. Using CYP bactosomes, we also demonstrate that CYP1A2 but not CYP1B1 or CYP3A4 has propensity for potentiating these compounds, indicating preference for CYP1A bioactivation.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1016/j.bmc.2021.116167en_US
dc.rights© 2021 Elsevier. Reproduced in accordance with the publisher's self-archiving policy. This manuscript version is made available under the CC-BY-NC-ND 4.0 license (https://creativecommons.org/licenses/by-nc-nd/4.0/)
dc.subjectCytochrome P450en_US
dc.subjectDuocarmycinen_US
dc.subjectBioactivationen_US
dc.subjectBioprecursoren_US
dc.subjectCytotoxicityen_US
dc.titleProbing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compoundsen_US
dc.status.refereedYesen_US
dc.date.Accepted2021-04-19
dc.date.application2021-04-21
dc.typeArticleen_US
dc.date.EndofEmbargo2022-04-21
dc.type.versionAccepted manuscripten_US
dc.description.publicnotesThe full-text of this article will be released for public view at the end of the publisher embargo 21 Apr 2022.
dc.date.updated2021-07-06T11:25:42Z
refterms.dateFOA2021-07-22T08:03:23Z
dc.openaccess.statusGreenen_US


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