Yes / The 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. / The authors would like to thank Yorkshire Cancer Research (Program grant B381PA) for supporting our work focused on exploring CYPs as targets for prodrug development. The human recombinant CYP1A1 was a gift from Prof Emily E. Scott, University of Michigan; the enzyme was produced via NIH funded grant (R37 GM076343).
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/19641 |
| Date | 05 October 2023 |
| Creators | Ortuzar, N., Karu, K., Presa, Daniela, Morais, Goreti R., Sheldrake, Helen M., Shnyder, Steven D., Barnieh, Francis M., Loadman, Paul, Patterson, Laurence H., Pors, Klaus, Searcey, M. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Accepted manuscript |
| Rights | © 2021 Published by Elsevier Ltd. All rights reserved. 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., CC-BY-NC-ND |
| Relation | https://doi.org/10.1016/j.bmc.2021.116167 |
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