Synthesis of the tumour-inhibitory alkaloids, ellipticine, 9-methoxyellipticine, and related pyrido[4,3-b]carbazoles

Dalton, LK; Demerac, S; Elmes, B. C.; Loder, JW; Swan, JM; Teitei, T

doi:10.1071/ch9672715

Cited by 221 publications

(98 citation statements)

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“…Ochrosia borbonica, Excavatia coccinea), and several its derivatives exhibit significant antitumor and anti-HIV activities [1][2][3] . This compound is one of the simplest naturally occurring alkaloids, having a planar structure 4 .…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová¹,

Rupertová²,

Schmeiser³

et al. 2006

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. This article reviews the mechanisms of predominant pharmacological and cytotoxic effects of ellipticine and shows the results of our laboratories indicating a novel mechanism of its action. The prevalent mechanisms of ellipticine antitumor, mutagenic and cytotoxic activities were suggested to be intercalation into DNA and inhibition of DNA topoisomerase II activity. We demonstrated a new mode of ellipticine action, formation of covalent DNA adducts mediated by its oxidation with cytochromes P450 (CYP) and peroxidases. The article reports the molecular mechanism of ellipticine oxidation by CYPs and identifies human and rat CYPs responsible for ellipticine metabolic activation and detoxication. It also presents a role of peroxidases (i.e. myeloperoxidase, cyclooxygenases, lactoperoxidase) in ellipticine oxidation leading to ellipticine-DNA adducts. The 9-hydroxy-and 7-hydroxyellipticine metabolites formed by CYPs and the major product of ellipticine oxidation by peroxidases, the dimer, in which the two ellipticine skeletons are connected via N 6 of the pyrrole ring of one ellipticine molecule and C9 in the second one, are the detoxication metabolites. On the contrary, 13-hydroxy-and 12-hydroxyellipticine, produced by ellipticine oxidation with CYPs, the latter one formed also spontaneously from another CYP-and peroxidase-mediated metabolite, ellipticine N 2 -oxide, are metabolites responsible for formation of two ellipticine-derived deoxyguanosine adducts in DNA. The results reviewed here allow us to propose species, two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating two major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.

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Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová¹,

Rupertová²,

Schmeiser³

et al. 2006

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…EPED3 is a hydrophilic derivative of ellipticine ( Fig. 1), a hydrophobic cell-permeable alkaloid originally derived from Apocyanaceae plants (12).…”

Section: Introductionmentioning

confidence: 99%

Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma

Tian

Landowski

Stephens

et al. 2008

Molecular Cancer Therapeutics

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“…1. Ellipticine 1 and isoellipticine 3 were synthesized according to previously described procedures (13,14). The synthesis of isomers 5 and 6 has been recently described (15,16).…”

Section: Methodsmentioning

confidence: 99%

Protonophoric Activity of Ellipticine and Isomers across the Energy-transducing Membrane of Mitochondria

Schwaller

Allard

Lescot

et al. 1995

Journal of Biological Chemistry

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Ellipticine is an antitumor alkaloid capable of uncoupling mitochondrial oxidative phosphorylation. It behaves as a lipophilic weak base with pK ‫؍‬ 7.40. We have investigated its molecular mode of action using several of its isomers with pK ranging between 5.8 and 7.7 and ellipticinium, which is a permanent cationic derivative. The effects of these molecules on mitochondrial oxygen uptake and transmembrane potential were compared at different pHs. Ellipticinium exhibited very low effects on both respiratory rate and membrane potential. By contrast, protonable derivatives showed maximal stimulation of oxygen uptake and depolarizing effects when the pH of the medium was close to the drug pK. These effects were lowered when the transmembrane ⌬pH was dissipated, which indicates that the neutral form of the drug is implicated in the uncoupling mechanism. In addition, protonable derivatives of ellipticine display a linear relationship between oxidation rate and transmembrane potential, which suggests that the uncoupling properties of these molecules result from a protonophoric mechanism. From these results, the following cyclic protonophoric mechanism is proposed for protonable ellipticines: (i) electrophoretical accumulation of the protonated form; (ii) deprotonation at the matrix interface; (iii) diffusion outwards; and (iv) reprotonation at the external interface.

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Synthesis of the tumour-inhibitory alkaloids, ellipticine, 9-methoxyellipticine, and related pyrido[4,3-b]carbazoles

Cited by 221 publications

References 0 publications

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma

Protonophoric Activity of Ellipticine and Isomers across the Energy-transducing Membrane of Mitochondria

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