Reversal of the regioselectivity of anthrapyrazole formation. A new synthesis of losoxantrone (DUP941)

Zhang, Linhua; Meier, W.; Watson, E. J.; Gibson, E. P.

doi:10.1016/s0040-4039(00)73069-3

Cited by 13 publications

(4 citation statements)

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“…To explore the possibility of pyrazole formation, quinone 4 was treated with hydrazine for an extended period, and the pyrazole 7 10 was obtained. As might be expected, 11 only a single carbonyl resonance was observed in the 13 C spectrum of this product.…”

Section: Introductionsupporting

confidence: 83%

Tripeptide Probes for Tripeptidyl Protease I Production via Gene Transfer

et al. 2003

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Tripeptides derived from 5-chloroanthraquinone hydrazide and anthraquinone hydrazide have been prepared as potential reagents to probe cellular expression of tripeptidyl protease I (TPP-I). Attempted chemical synthesis of Gly-l-Pro-l-Ala-chloroanthraquinone hydrazide, a compound that had been reported to serve as a substrate for this enzyme, was complicated by formation of a pyrazoloquinone. In contrast, formation of pyrazoloquinones was not observed during coupling reactions with anthraquinone hydrazide, and several tripeptide derivatives of this compound were prepared. The most attractive probe for TPP-I activity in tests with mouse kidney tissue sections proved to be Gly-l-Pro-l-Ser anthraquinone hydrazide.

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Section: Introductionsupporting

confidence: 83%

Tripeptide Probes for Tripeptidyl Protease I Production via Gene Transfer

et al. 2003

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“…Both the synthetic preparation and the exceptional in vivo anticancer activity of losoxantrone are well known (Lown, 1983;Showalter et al, 1987;Reszka et al, 1988;Beylin et al, 1989;Fry, 1991;Calvert et al, 1994;Zhang et al, 1994). Several clinical studies of combination regimens with losoxantrone and paclitaxel in patients with advanced breast cancer were recently completed (Kaufman et al, 1998(Kaufman et al, , 1999Diab et al, 1999).…”

Section: Losoxantrone 7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5mentioning

confidence: 99%

“…The cardiotoxicity represents the dosis-limiting side effect and is induced by free radicals created during the biotransformation of anthraquinonoid antitumor agents (Murdock et al, 1979;Smith, 1983;Zee-Cheng and Cheng, 1983) (Fig. 1).Both the synthetic preparation and the exceptional in vivo anticancer activity of losoxantrone are well known (Lown, 1983;Showalter et al, 1987;Reszka et al, 1988;Beylin et al, 1989;Fry, 1991;Calvert et al, 1994;Zhang et al, 1994). Several clinical studies of combination regimens with losoxantrone and paclitaxel in patients with advanced breast cancer were recently completed (Kaufman et al, 1998(Kaufman et al, , 1999Diab et al, 1999).…”

mentioning

confidence: 99%

The Oxidative Biotransformation of Losoxantrone (CI-941)

Renner

Piperopoulos²,

Gebhardt³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The oxidative biotransformation of the anticancer drug 7-hydroxy- 2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino]ethyl]amino]anthra[1,9-cd]pyrazol-6(2H)-one dihydrochloride (losoxantrone, CI-941) after incubation of primary cultures of rat hepatocytes has been investigated. The structures of twelve losoxantrone metabolites have been elucidated by means of highperformance liquid chromatography-mass spectometry, tandem mass spectrometry, and two-dimensional NMR. In these mammalian hepatocytes, the CI-941 biotransformation includes a monohydroxylation of the phenolic substructure of the CI-941-chromophore via cytochrome P450 catalysis, resulting in metabolites having an orthoand para-hydroquinonoid substructure, respectively. The identification of a glutathione conjugate as a follow-up metabolite confirms the oxidative activation of the ortho-hydroxylated losoxantrone metabolite. The oxidative activation establishes the ability of CI-941 to form covalent bonds to intracellular nucleophilic targets. Furthermore, the CI-941 metabolism was shown to be extremely suppressed in rat hepatocytes incubated with metyrapone. In contrast to these results, human tumor HepG2 cells did not show any CI-941 biotransformation after incubation., is a member of the novel class of anthrapyrazole anticancer agents. This cytostatic compound is derived from anthracyclines (e.g., doxorubicin and daunorubicin) and mitoxantrone by chromophore modification of the anthracene-9,10-dione unit. In clinical trials (phase I and II), losoxantrone has been shown to be the most powerful anthrapyrazole. It was developed with the intention of diminishing the cardiotoxicity associated with anthracene-9,10-dione drugs. The cardiotoxicity represents the dosis-limiting side effect and is induced by free radicals created during the biotransformation of anthraquinonoid antitumor agents (Murdock et al., 1979;Smith, 1983;Zee-Cheng and Cheng, 1983) (Fig. 1).Both the synthetic preparation and the exceptional in vivo anticancer activity of losoxantrone are well known (Lown, 1983;Showalter et al., 1987;Reszka et al., 1988;Beylin et al., 1989;Fry, 1991;Calvert et al., 1994;Zhang et al., 1994). Several clinical studies of combination regimens with losoxantrone and paclitaxel in patients with advanced breast cancer were recently completed (Kaufman et al., 1998(Kaufman et al., , 1999Diab et al., 1999). Furthermore, the results of a phase II clinical trail in hormone-refractory metastatic prostate cancer were published (Huan et al., 2000).The antitumor activity of losoxantrone, among other biochemical effects against tumor cells, is based on inhibiting the enzyme topoisomerase II (Fry, 1991;Leteurtre et al., 1994). Although numerous studies analyzing the pharmacokinetic behavior of the drug under various conditions were published, the metabolism of anthrapyrazole CI-941 is almost unknown until now. Only a small part of the CI-941 biotransformation, proved by metabolites in human urine Richards and Sun, 1995) and feces (Joshi et al., 2001), was ...

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“…In the case of compound 3 , under the above-mentioned conditions, a complex crude mixture was obtained. However, in the absence of catalyst and using DMA/THF as solvent, a fairly high yield of compound 4 was achieved (Table ).…”

mentioning

confidence: 99%

Regioselective Synthesis of 1-Alkyl- or 1-Aryl-1H-indazoles via Copper-Catalyzed Cyclizations of 2-Haloarylcarbonylic Compounds

et al. 2007

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[reaction: see text] A general method for the one-step regioselective synthesis of 1-alkyl- or 1-aryl-1H-indazoles from ortho-halogenated alkanoylphenones, benzophenones, and arylcarboxylic acids, via copper-catalyzed amination, was developed by using 0.2% mol of CuO in the presence of K(2)CO(3). The reaction involves amination followed by intramolecular dehydration. Different functionalized alkyl aryl ketones, diaryl ketones, and benzoic acid derivatives were efficiently coupled with several hydrazines. Ligands commonly employed as catalysts for intermolecular amination were shown to be ineffective for this cyclization.

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Reversal of the regioselectivity of anthrapyrazole formation. A new synthesis of losoxantrone (DUP941)

Cited by 13 publications

References 4 publications

Tripeptide Probes for Tripeptidyl Protease I Production via Gene Transfer

Tripeptide Probes for Tripeptidyl Protease I Production via Gene Transfer

The Oxidative Biotransformation of Losoxantrone (CI-941)

Regioselective Synthesis of 1-Alkyl- or 1-Aryl-1H-indazoles via Copper-Catalyzed Cyclizations of 2-Haloarylcarbonylic Compounds

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