Human and rat urinary metabolites of the antitumor drug celiptium ® (N2-methyl-9-hydroxyellipticinium acetate, NSC 264137). Identification of cysteine conjugates supporting the “biooxidative alkylation” hypothesis

Monsarrat, Bernard; Maftouh, Mohamed; Meunier, Gérard; Dugue, Bernard; Bernadou, Jean; Armand, Jean‐Pierre; Picard-Fraire, C.; Meunier, Bernard; Paoletti, Claude

doi:10.1016/0006-2952(83)90171-5

Cited by 22 publications

(4 citation statements)

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“…69 Cysteine conjugates of the antitumor agent elliptinium acetate (8.69) found in the urine of patients taking the drug indicate that an oxidative mechanism is important (Scheme 8.18) and suggest that alkylation, as well as intercalation, of DNA by 8.69 may be a viable mechanism of action. 70 …”

Section: 65mentioning

confidence: 99%

Prodrugs and Drug Delivery Systems

Silverman

1992

The Organic Chemistry of Drug Design and Drug Action

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Section: 65mentioning

confidence: 99%

Prodrugs and Drug Delivery Systems

Silverman

1992

The Organic Chemistry of Drug Design and Drug Action

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“…Evidence for the occurrence of the oxidative bioactivation of NMHE in vivo was provided by the detection of the glutathione-NMHE adduct in biological fluids such as bile and urine of patients and animals treated with the drug (Monsarrat et al, 1983;Maftouh et al, 1984). Consequently, hypotheses concerning the mechanism of the cytotoxicity of NMHE should take into account its possible covalent binding to biological nucleophiles.…”

mentioning

confidence: 99%

Peroxidase-catalyzed covalent binding of the antitumor drug N2-methyl-9-hydroxyellipticinium to DNA in vitro

Auclair¹,

Dugue²,

Meunier³

et al. 1986

Biochemistry

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In the presence of DNA, the antitumor drug N2-methyl-9-hydroxyellipticinium (elliptinium; NMHE) [Le Pecq, J. B., Gosse, C., Dat-Xuong, N., & Paoletti, C. (1975) C. R. Seances Acad. Sci., Ser. D 281, 1365-1367] is oxidized by the horseradish peroxidase-hydrogen peroxide (HRP-H2O2) system to the quinone imine derivative N2-methyl-9-oxoellipticinium (NMOE) [Auclair, C., & Paoletti, C. (1981) J. Med. Chem. 24, 289-295], which interacts with DNA according to the intercalation mode. When excess H2O2 was used, the major part of the quinone imine was further oxidized to the o-quinone N2-methyl-9,10-dioxoellipticinium [Bernadou, J., Meunier, G., Paoletti, C., & Meunier, B. (1983) J. Med. Chem. 26, 574-579]. In the presence of stoichiometric amounts of H2O2 (H2O2/NMHE = 1), NMOE reacts with DNA, yielding a fluorescent compound irreversibly linked to the nucleic acid, which is related to the covalent binding of the ellipticinium chromophore. Under optimal reaction conditions, NMHE binding occurs according to a first-order process (k = 4.3 X 10(-3) min-1) with a linear increase with respect to drug to nucleotide ratio up to a maximum binding of 1 NMHE per 20 base pairs (r = 0.05). The fluorescence spectra (ex, 330 nm; em, 548 nm) of NMHE bound to DNA, the occurrence of energy transfer from the DNA to the drug, and the DNA length increase of the DNA-NMHE adduct suggest that the binding occurs at the intercalating site with limited denaturation of the DNA helix.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Concentrated filtrate was subject to LC separation on a silica gel column (Lobar size C column from E. Merck) using solvent system A. Elution was constantly monitored at 307 nm in a flow-through cell using a Gilford Model 250 spectrophotometer. Fractions containing 3a were combined and evaporated to result in 473 mg of solid (yield, (9) 51%). The analytical sample was crystallized from EtOAc: Rf 0.23 (A); mp 178.0-180.3 °C; NMR (CDC13) 8.27 (s, br, 1 , NH), 5-Chloro-2-[3-(acetaminomethyl)-5-methyl-4H-l,2,4-triazol-4-yl]benzophenone (3b) and 5-Chloro-2-[3-(hemisuccinaminomethyl)-5-methyl-4/f-l,2,4-triazol-4-yl]benzophenone (3c).…”

Section: Methodsmentioning

confidence: 99%

Sequentially labile water-soluble prodrugs of alprazolam

Cho¹,

Sethy²,

Haynes³

1986

J. Med. Chem.

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A 1,4-benzodiazepine analogue alprazolam (1) undergoes ring-opening hydrolysis under acidic conditions to form a triazolobenzophenone (2). At a neutral pH, 2 rapidly and quantitatively cyclizes back to 1. This facile reversible reaction was utilized in developing water-soluble prodrugs of 1 in which the "solubility anchoring" acyl moieties are formyl, acetyl, succinyl, glycyl, leucyl, and gamma-aminobutyryl groups. These compounds were prepared directly from 2 and corresponding acids through DCC coupling in a 1:1 mixture of H2O and THF. They should be stable in aqueous media at room temperature. Promoieties used should be nontoxic at an intended dose level. In vitro human serum hydrolysis study showed that only glycyl and leucyl amides were able to regenerate 1 within a reasonable period of time. Ex vivo competitive receptor binding assay in mice with [3H]flunitrazepam indicated that leucyl amide prodrug should be able to produce a rapid onset of the intrinsic central nervous system activity of 1 when parenterally administered. For all compounds studied, the final outcome of the biological response appears to be kinetically controlled, rather than by an unfavorable equilibrium, particularly by the first step in which the amide bond is hydrolyzed in vivo.

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Human and rat urinary metabolites of the antitumor drug celiptium ® (N2-methyl-9-hydroxyellipticinium acetate, NSC 264137). Identification of cysteine conjugates supporting the “biooxidative alkylation” hypothesis

Cited by 22 publications

References 4 publications

Prodrugs and Drug Delivery Systems

Prodrugs and Drug Delivery Systems

Peroxidase-catalyzed covalent binding of the antitumor drug N2-methyl-9-hydroxyellipticinium to DNA in vitro

Sequentially labile water-soluble prodrugs of alprazolam

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