A Two‐Step Synthesis of Cytostatically Active Benzo[c]phenanthridine Derivatives.

Clement, Bernd; Weide, Matthias; Wolschendorf, Ulrich; Kock, Ilka

doi:10.1002/chin.200523142

Cited by 2 publications

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“…In contrast to synthetic methods already published, [3][4][5] we found a more efficient synthesis for benzo[c]phenanthridine derivatives with an exocyclic primary amine group ortho to the endocyclic nitrogen. 6,7 We have reported previously about the synthesis of the benzo[c]phenanthridine derivatives 1, 4, 6, 8, 32, and 37 and showed some preliminary data including cytotoxic properties. 7 In this paper, we present the synthesis of a series of 11substituted 6-aminobenzo[c]phenanthridines and corresponding dihydro derivatives (Figure 2) as potential antitumor agents.…”

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confidence: 99%

“…6,7 We have reported previously about the synthesis of the benzo[c]phenanthridine derivatives 1, 4, 6, 8, 32, and 37 and showed some preliminary data including cytotoxic properties. 7 In this paper, we present the synthesis of a series of 11substituted 6-aminobenzo[c]phenanthridines and corresponding dihydro derivatives (Figure 2) as potential antitumor agents. Selected compounds were evaluated in terms of their cytotoxicity and antitumor properties in the in vitro anticancer screening and the in vivo hollow fiber assay of the National Cancer Institute.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of 11-Substituted 6-Aminobenzo[c]phenanthridine Derivatives, a New Class of Antitumor Agents

et al. 2005

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The synthesis of 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines and 11-substituted 6-aminobenzo[c]phenanthridines through an efficient method is described. The antiproliferative activity of selected compounds against a wide panel of tumor cell lines was tested in the in vitro anticancer screening and the in vivo hollow fiber assay of the National Cancer Institute. Several compounds turned out to exhibit considerable cytotoxicity for tumor cells. For the study of structure-activity relationships different substituents were introduced in the 11-position. Compounds with methoxyphenyl substituents tended to show the highest potency. Several compounds exhibited noteworthy antitumor activity with GI(50) values across all cell lines <1 microM. 6-Amino-11-(3,4,5-trimethoxyphenyl)benzo[c]phenanthridine perchlorate was the most potent agent in the NCI's in vivo hollow fiber assay. Most of the tested compounds showed a remarkable selectivity for leukemia, breast cancer, and prostate cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 11-Substituted 6-Aminobenzo[c]phenanthridine Derivatives, a New Class of Antitumor Agents

et al. 2005

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“…1989). In our laboratory we developed a very short synthetic route to benzo[ c ]phenanthridine derivatives with an exocyclic primary amine group in the ortho position to the endocyclic nitrogen (Clement et al . 2005; Kock et al .…”

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Inhibitory Effects of Cytostatically Active 6‐Aminobenzo[c]phenanthridines on Cytochrome P450 Enzymes in Human Hepatic Microsomes

Zebothsen

Kunze

Clement

2006

Basic Clin Pharma Tox

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Besides assays for the evaluation of efficacy new drug candidates have to undergo extensive testings for enhancement of pharmaceutical drug safety and optimization of application. The objective of the present work was to investigate the pharmacokinetic drug drug interaction potential for the cytostatically active 6-aminobenzo[c]phenanthridines benzo[c]phenanthridine) and 4,benzo[c]phenanthridine) in vitro through incubation with human hepatic microsomes and marker substrates. For these studies the cytochrome P-450 isoenzymes and corresponding marker substrates recommended by the EMEA (The European Agency for the Evaluation of Medicinal Products) were chosen. In detail these selective substrates were caffeine (CYP1A2), coumarin (CYP2A6), tolbutamide (CYP2C9), S-(π)-mephenytoin (CYP2C19), dextromethorphane (CYP2D6), chlorzoxazone (CYP2E1) and testosterone (CYP3A4). Incubations with each substrate were carried out without a possible inhibitor and in the presence of a benzo[c]phenanthridine or a selective inhibitor at varying concentrations. Marker activities were determined by HPLC (high performance liquid chromatography). For the isoenzymes showing more than 50% inhibition by the addition of 20 mM BP-11 or BP-D7 additional concentrations of substrate and inhibitor were tested for a characterization of the inhibition. The studies showed a moderate risk for BP-11 for interactions with the cytochrome P-450 isoenzymes CYP1A2, CYP2C9, CYP2D6 and CYP3A4. BP-D7, the compound with the highest cytotstatic efficacy, showed only a moderate risk for interactions with drugs, also metabolized by CYP3A4.Benzo[c]phenanthridine derivatives are a class of substances possessing a broad spectrum of pharmacological activities. In the literature many alkaloids with a benzo[c]phenanthridine ring system and interesting biological properties are mentioned. Especially antitumoural, cytotoxic and antileukaemic activities have been described for members of that group of alkaloids like for example fagaronine (Simeon et al. 1989). In our laboratory we developed a very short synthetic route to benzo[c]phenanthridine derivatives with an exocyclic primary amine group in the ortho position to the endocyclic nitrogen Kock et al. 2005). The NCI (National Cancer Institute, Bethesda, USA) results of the in vitro efficacy tests against 60 different tumour cell lines show meangraph midpoints (MG-MID) as averaged activity parameters for the 50% growth inhibitory concentration (GI 50 ) of 0.98 mM for BP-11 (6-amino-11,12-dihydro-11-(4-hydroxy-3,5-dimethoxyphenyl)benzo[c]phenanthridine) and 0.28 mM for BP-D7 (6-amino-11-(3,4,5-trimethoxyphenyl)benzo[c]phenanthridine) ( fig. 1). These results demonstrate a better activity for our compounds than for fagaronine. BP-D7 showed excellent in vivo activity as well

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A Two‐Step Synthesis of Cytostatically Active Benzo[c]phenanthridine Derivatives.

Cited by 2 publications

References 1 publication

Synthesis and Biological Evaluation of 11-Substituted 6-Aminobenzo[c]phenanthridine Derivatives, a New Class of Antitumor Agents

Synthesis and Biological Evaluation of 11-Substituted 6-Aminobenzo[c]phenanthridine Derivatives, a New Class of Antitumor Agents

Inhibitory Effects of Cytostatically Active 6‐Aminobenzo[c]phenanthridines on Cytochrome P450 Enzymes in Human Hepatic Microsomes

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