Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds

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Ortuzar, Natalia, Karu, Kersti, Presa, Daniela, Morais, Goreti R., Sheldrake, Helen M., Shnyder, Steve D., Barnieh, Francis M., Loadman, Paul M., Patterson, Laurence H., Pors, Klaus and Searcey, Mark (2021) Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds. Bioorganic & Medicinal Chemistry, 40. ISSN 0968-0896

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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.

Item Type:	Article
Uncontrolled Keywords:	bioactivation,bioprecursor,cytochrome p450,cytotoxicity,duocarmycin,drug discovery,molecular medicine,molecular biology,biochemistry,clinical biochemistry,pharmaceutical science,organic chemistry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/3000/3002
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024)
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Related URLs:	http://www.scopus.com/inward/record.url?... https://linkinghub.elsevier.com/retrieve...
Depositing User:	LivePure Connector
Date Deposited:	23 Apr 2021 23:49
Last Modified:	28 Mar 2025 10:39
URI:	https://ueaeprints.uea.ac.uk/id/eprint/79866
DOI:	10.1016/j.bmc.2021.116167

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