83329-79-7Relevant academic research and scientific papers
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
experimental part, p. 1075 - 1085 (2012/08/13)
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.
An Efficient Synthesis of C-11 Substituted 6H-PyridoCarbazoles
Modi, Sandeep P.,Michael, Meged A.,Archer, Sydney,Carey, James J.
, p. 6539 - 6548 (2007/10/02)
A synthesis of the natural product 5-methyl-6H-pyridocarbazole-11-methanol, 5 from the ketolactam 7 is described.Compound 7 was treated with one equivalent of MeLi followed by quenching of the reaction mixture with water to give the lactone 19.Compound 19 was treated with a number of organolithium reagents such as methyllithium, n-butyllithium, ethoxyvinyl lithium and the lithio derivative of formaldehyde diethyl mercaptal to give, after sodium borohydride reduction, 1, 15, 30, and 31 respectively.Compounds 30 and 31 were hydrolyzed and then reduced to give compounds 5 and 6 respectively, in an overall yield of 21percent.Compounds 16 and 22 were identified as the intermediates in the Saulnier-Gribble synthesis of ellipticine. Key Words: Ellipticine; 9-Methoxy-ellipticine; PyridoCarbazole; Natural Product; Antitumor Agents
SYNTHESIS OF 5-METHYL-6H-PYRIDOCARBAZOLE-11-METHANOL
Modi, Sandeep P.,Carey, James J.,Archer, Sydney
, p. 5845 - 5848 (2007/10/02)
The structures of some of the intermediates in Saulnier-Gribble synthesis of ellipticine have been determined.One of the intermediates 8 has been converted to 5-methyl-6H-pyridocarbazole-11-methanol, an alkaloid isolated from Strychnos dinklagei.
