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

被引：4

作者：

Ortuzar, Natalia ^{[1
]}

Karu, Kersti ^{[1
]}

Presa, Daniela ^{[2
]}

Morais, Goreti R. ^{[2
]}

Sheldrake, Helen M. ^{[2
]}

Shnyder, Steve D. ^{[2
]}

Barnieh, Francis M. ^{[2
]}

Loadman, Paul M. ^{[2
]}

Patterson, Laurence H. ^{[2
]}

Pors, Klaus ^{[2
]}

Searcey, Mark ^{[3
]}

机构：

[1] UCL Sch Pharm, Dept Pharmaceut & Biol Chem, 29-39 Brunswick Sq, London WC1N 1AX, England

[2] Univ Bradford, Fac Life Sci, Sch Pharm & Med Sci, Inst Canc Therapeut, Bradford BD7 1DP, W Yorkshire, England

[3] Univ East Anglia, Sch Pharm, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2021年 / 40卷

关键词：

Cytochrome P450; Duocarmycin; Bioactivation; Bioprecursor; Cytotoxicity; PYRINDAMYCIN ALKYLATION SUBUNIT; PHASE-I; DNA ALKYLATION; CC-1065; IDENTIFICATION; PHARMACOPHORE; ACTIVATION; MECHANISMS; BIZELESIN; ANALOGS;

D O I：

10.1016/j.bmc.2021.116167

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：8

共 36 条

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