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

• Published in: Bioorganic & medicinal chemistry Vol. 40; pp. 116167 - 116174
• Main Authors: 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, Searcey, Mark
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.06.2021; Elsevier
• Subjects: Bioactivation; Biochemistry & Molecular Biology; Bioprecursor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cytochrome P450; Cytotoxicity; Duocarmycin; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Duocarmycin; Cytotoxicity; Bioprecursor; Cytochrome P450; Bioactivation; DNA ALKYLATION; PYRINDAMYCIN ALKYLATION SUBUNIT; ACTIVATION; ANALOGS; MECHANISMS; CC-1065; IDENTIFICATION; BIZELESIN; PHARMACOPHORE; PHASE-I
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2021.116167

[Display omitted] 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.