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

Natalia Ortuzar; Kersti Karu; Daniela Presa; Goreti R. Morais; Helen M. Sheldrake; Steve D. Shnyder; Francis M. Barnieh; Paul M. Loadman; Laurence H. Patterson; Klaus Pors; Mark Searcey

doi:10.1016/j.bmc.2021.116167

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

Natalia Ortuzar, Kersti Karu, Daniela Presa, Goreti R. Morais, Helen M. Sheldrake, Steve D. Shnyder, Francis M. Barnieh, Paul M. Loadman, Laurence H. Patterson, Klaus Pors, Mark Searcey

Norwich Institute for Healthy Aging

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	116167
Journal	Bioorganic & Medicinal Chemistry
Volume	40
Early online date	21 Apr 2021
DOIs	https://doi.org/10.1016/j.bmc.2021.116167
Publication status	Published - 15 Jun 2021

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10.1016/j.bmc.2021.116167

Accepted_ManuscriptAccepted author manuscript, 646 KBLicence: CC BY-NC-ND

https://linkinghub.elsevier.com/retrieve/pii/S0968089621001759

Cite this

Ortuzar, N., Karu, K., Presa, D., Morais, G. R., Sheldrake, H. M., Shnyder, S. D., Barnieh, F. M., Loadman, P. M., Patterson, L. H., Pors, K., & Searcey, M. (2021). Probing cytochrome P450 (CYP) bioactivation with chloromethylindoline bioprecursors derived from the duocarmycin family of compounds. Bioorganic & Medicinal Chemistry, 40, [116167]. https://doi.org/10.1016/j.bmc.2021.116167

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

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.",

author = "Natalia Ortuzar and Kersti Karu and Daniela Presa and Morais, {Goreti R.} and Sheldrake, {Helen M.} and Shnyder, {Steve D.} and Barnieh, {Francis M.} and Loadman, {Paul M.} and Patterson, {Laurence H.} and Klaus Pors and Mark Searcey",

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AU - Ortuzar, Natalia

AU - Karu, Kersti

AU - Presa, Daniela

AU - Morais, Goreti R.

AU - Sheldrake, Helen M.

AU - Shnyder, Steve D.

AU - Barnieh, Francis M.

AU - Loadman, Paul M.

AU - Patterson, Laurence H.

AU - Pors, Klaus

AU - Searcey, Mark

PY - 2021/6/15

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AB - 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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