108320-78-1Relevant articles and documents
Cytochrome b5 increases cytochrome P450 3A4-mediated activation of anticancer drug ellipticine to 13-hydroxyellipticine whose covalent binding to DNA is elevated by sulfotransferases and N,O-acetyltransferases
Stiborova, Marie,Indra, Radek,Moserova, Michaela,Cerna, Vera,Rupertova, Martina,Martinek, Vaclav,Eckschlager, Tomas,Kizek, Rene,Frei, Eva
, p. 1075 - 1085 (2012)
The antineoplastic alkaloid ellipticine is a prodrug, whose pharmacological efficiency is dependent on its cytochrome P450 (P450)- and/or peroxidase-mediated activation in target tissues. The P450 3A4 enzyme oxidizes ellipticine to five metabolites, mainly to 13-hydroxy- and 12- hydroxyellipticine, the metabolites responsible for the formation of ellipticine-13-ylium and ellipticine-12-ylium ions that generate covalent DNA adducts. Cytochrome b5 alters the ratio of ellipticine metabolites formed by P450 3A4. While the amounts of the detoxication metabolites (7-hydroxy- and 9-hydroxyellipticine) were not changed with added cytochrome b5, 12-hydroxy- and 13-hydroxyellipticine, and ellipticine N 2-oxide increased considerably. The P450 3A4-mediated oxidation of ellipticine was significantly changed only by holo-cytochrome b5, while apo-cytochrome b5 without heme or Mn-cytochrome b5 had no such effect. The change in amounts of metabolites resulted in an increased formation of covalent ellipticine-DNA adducts, one of the DNA-damaging mechanisms of ellipticine antitumor action. The amounts of 13-hydroxy- and 12-hydroxyellipticine formed by P450 3A4 were similar, but more than 7-fold higher levels of the adduct were formed by 13-hydroxyellipticine than by 12-hydroxyellipticine. The higher susceptibility of 13-hydroxyellipticine toward heterolytic dissociation to ellipticine-13-ylium in comparison to dissociation of 12-hydroxyellipticine to ellipticine-12-ylium, determined by quantum chemical calculations, explains this phenomenon. The amounts of the 13- hydroxyellipticine-derived DNA adduct significantly increased upon reaction of 13-hydroxyellipticine with either 3′-phosphoadenosine-5′- phosphosulfate or acetyl-CoA catalyzed by human sulfotransferases 1A1, 1A2, 1A3, and 2A1, or N,O-acetyltransferases 1 and 2. The calculated reaction free energies of heterolysis of the sulfate and acetate esters are by 10-17 kcal/mol more favorable than the energy of hydrolysis of 13-hydroxyellipticine, which could explain the experimental data.
CHEMISTRY OF 6H-PYRIDOCARBAZOLES. PART 12. SYNTHESIS OF POTENTIAL BISINTERCALATING DRUGS BEARING TWO ELLIPTICINE UNITS
Ratcliffe, Andrew J.,Sainsbury, Malcolm,Smith, Andrew D.,Scopes, David I. C.
, p. 2933 - 2944 (2007/10/02)
A number of bisellipticines have been synthesized in an attempt to increase the potency of the parent tetracycles as anti-cancer drugs through bis-intercalation into the same strand of DNA.The compounds described are structures in which two pyridoc
SYNTHESIS OF 5-HYDROXYMETHYL-11-METHYL-6H-PYRIDOCARBAZOLE AND 5-FORMYL-11-METHYL-6H-PYRIDOcarbazole (17-OXOELLIPTICINE)
Ross, Bruce S.,Archer, Sydney
, p. 5343 - 5346 (2007/10/02)
A synthesis of 5-hydroxymethyl-11-methyl-6H-pyridocarbazole and the corresponding 5-formyl derivative, 17-oxoellipticine, is described, the key feature of which is the use of the Krohnke aldehyde synthesis to effect the debenzylation of a p-nitrobe
