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Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds
Ortuzar, N. Karu, K. Presa, Daniela Morais, Goreti R. Sheldrake, Helen M. Patterson, Laurence H. Pors, Klaus
Ortuzar, N.
Karu, K.
Presa, Daniela
Morais, Goreti R.
Sheldrake, Helen M.
Patterson, Laurence H.
Pors, Klaus
Publication Date
2021-06-15
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© 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/)
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openAccess
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2021-04-19
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Abstract
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.
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Accepted manuscript
Citation
Ortuzar 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.
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