Ring D modifications of ellipticine. Part 2. Chlorination of ellipticine via its N-oxide and synthesis and selective acetylation of 5,6,11-trimethyl-5H-benzo[b]carbazole.

Boogaard, A. T.; Pandit, U. K.; Koomen, Gerrit‐Jan

doi:10.1016/s0040-4020(01)85018-3

Cited by 22 publications

(8 citation statements)

References 33 publications

(4 reference statements)

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“…The 7-hydroxyellipticine and ellipticine N 2 -oxide were synthesized as described previously (9,10). Enzymes and chemicals for the 32 P-postlabeling assay were obtained from sources described previously (1,(3)(4)(5).…”

Section: Chemicals and Reagents Ellipticine Nadpmentioning

confidence: 99%

The Anticancer Drug Ellipticine Forms Covalent DNA Adducts, Mediated by Human Cytochromes P450, through Metabolism to 13-Hydroxyellipticine and EllipticineN2-Oxide

et al. 2004

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Ellipticine is an antineoplastic agent, the mode of action of which is considered to be based on DNA intercalation and inhibition of topoisomerase II. We found that ellipticine also forms the cytochrome P450 (CYP)-mediated covalent DNA adducts. We now identified the ellipticine metabolites formed by human CYPs and elucidated the metabolites responsible for DNA binding. The 7-hydroxyellipticine, 9-hydroxyellipticine, 12-hydroxyellipticine, 13-hydroxyellipticine, and ellipticine N 2 -oxide are generated by hepatic microsomes from eight human donors. The role of specific CYPs in the oxidation of ellipticine and the role of the ellipticine metabolites in the formation of DNA adducts were investigated by correlating the levels of metabolites formed in each microsomal sample with CYP activities and with the levels of the ellipticine-derived deoxyguanosine adducts in DNA. On the basis of this analysis, formation of 9-hydroxyellipticine and 7-hydroxyellipticine was attributable to CYP1A1/2, whereas production of 13-hydroxyellipticine and ellipticine N 2 -oxide, the metabolites responsible for formation of two major DNA adducts, was attributable to CYP3A4. Using recombinant human enzymes, oxidation of ellipticine to 9-hydroxyellipticine and 7-hydroxyellipticine by CYP1A1/2 and to 13-hydroxyellipticine and N 2 -oxide by CYP3A4 was corroborated. Homologue modeling and docking of ellipticine to the CYP3A4 active center was used to explain the predominance of ellipticine oxidation by CYP3A4 to 13-hydroxyellipticine and N 2 -oxide.

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Section: Chemicals and Reagents Ellipticine Nadpmentioning

confidence: 99%

The Anticancer Drug Ellipticine Forms Covalent DNA Adducts, Mediated by Human Cytochromes P450, through Metabolism to 13-Hydroxyellipticine and EllipticineN2-Oxide

et al. 2004

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“…All these and other chemicals from commercial sources used in the experiments were reagent grade or better. 7-Hydroxyellipticine and the N 2 -oxide of ellipticine were synthesized as described previously (Wijsmuller et al, 1986;Boogaard et al, 1994) by J. Kučka (Charles University, Prague, Czech Republic); their purity was Ͼ99.5% as estimated by high-performance liquid chromatography (HPLC). Enzymatically prepared 12-hydroxy-and 13-hydroxyellipticine were obtained from multiple HPLC runs of ethyl acetate extracts of incubations of ellipticine with human and/or rat hepatic microsomes as described previously .…”

Section: Chemicals Nadpmentioning

confidence: 99%

The Anticancer Drug Ellipticine Is a Potent Inducer of Rat Cytochromes P450 1A1 and 1A2, Thereby Modulating Its Own Metabolism

Aimová

Svobodová²,

Kotrbová³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Ellipticine is an antineoplastic agent whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II, and formation of covalent DNA adducts mediated by cytochromes P450 (P450s) and peroxidases. Here, this drug was found to induce CYP1A1 and/or 1A2 enzymes and their enzymatic activities in livers, lungs, and kidneys of rats treated (i.p.) with ellipticine. The induction is transient. In the absence of repeated administration of ellipticine, the levels and activities of the induced CYP1A decreased almost to the basal level 2 weeks after treatment. The ellipticine-mediated CYP1A induction increases the DNA adduct formation by the compound. When microsomal fractions from livers, kidneys, and lungs of rats treated with ellipticine were incubated with ellipticine, DNA adduct formation, measured by 32 Ppostlabeling analysis, was up to 3.8-fold higher in incubations with microsomes from pretreated rats than with controls. The observed stimulation of DNA adduct formation by ellipticine was attributed to induction of CYP1A1 and/or 1A2-mediated increase in ellipticine oxidative activation to 13-hydroxy-and 12-hydroxyellipticine, the metabolites generating two major DNA adducts in human and rat livers. In addition to these metabolites, increased formation of the excretion products 9-hydroxy-and 7-hydroxyellipticine was also observed in microsomes of rats treated with ellipticine. Taken together, these results demonstrate for the first time that by inducing CYP1A1/2, ellipticine increases its own metabolism, leading both to an activation of this drug to reactive species-forming DNA adducts and to detoxication metabolites, thereby modulating to some extent its pharmacological and/or genotoxic potential.

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“… 38 , 43 We used 21b as a key intermediate for the targeted synthesis of a deaza analogue of the natural product 9-methoxyellipticine ( Scheme 4 a), producing 26 in three steps and in an overall yield of 20%. 44 …”

Section: Resultsmentioning

confidence: 99%

A Chemo- and Regioselective Tandem [3 + 2]Heteroannulation Strategy for Carbazole Synthesis: Combining Two Mechanistically Distinct Bond-Forming Processes

et al. 2022

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A modular approach to prepare tri- and tetracyclic carbazoles by a sequential [3 + 2]heteroannulation is described. First, optimization of Pd-catalyzed Buchwald–Hartwig amination followed by C/N-arylation in a one-pot process is established. Second, mechanistic analyses identified the origins of chemo- and regioselective sequential control of both bond-forming steps. Finally, the substrate scope is demonstrated by the preparation of a range of tri- and tetracyclic carbazoles, including expedient access to several natural products and anti-cancer agents.

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Ring D modifications of ellipticine. Part 2. Chlorination of ellipticine via its N-oxide and synthesis and selective acetylation of 5,6,11-trimethyl-5H-benzo[b]carbazole.

Cited by 22 publications

References 33 publications

The Anticancer Drug Ellipticine Forms Covalent DNA Adducts, Mediated by Human Cytochromes P450, through Metabolism to 13-Hydroxyellipticine and EllipticineN2-Oxide

The Anticancer Drug Ellipticine Forms Covalent DNA Adducts, Mediated by Human Cytochromes P450, through Metabolism to 13-Hydroxyellipticine and EllipticineN2-Oxide

The Anticancer Drug Ellipticine Is a Potent Inducer of Rat Cytochromes P450 1A1 and 1A2, Thereby Modulating Its Own Metabolism

A Chemo- and Regioselective Tandem [3 + 2]Heteroannulation Strategy for Carbazole Synthesis: Combining Two Mechanistically Distinct Bond-Forming Processes

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