Synthesis and PC3 androgen-independent prostate cells antiproliferative effect of fagaronine derivatives

Vanquelef, Enguerran; Hélesbeux, Jean-Jacques; Duval, Olivier; Débiton, Eric; Barthomeuf, Chantal; Jarry, Christian; Forfar, Isabelle; Richomme, Pascal

doi:10.1080/14756360701485901

Cited by 4 publications

(4 citation statements)

References 15 publications

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“…26) However, when the same method was used for preparation of 4-1 from 3-1, the reaction only gave less than 10% yield, and most of 3-1 was recovered. Next, the iodine oxidation 34) was also tested but without encouraging result.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and <i>in Vitro</i> Antifungal Activities of New 2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromides

Yang

Yao

Qin

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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2-Aryl-3,4-dihydroisoquinolin-2-iums might be considered as a class of simple analogues of natural quaternary benzo[c]phenanthridine alkaloids. In this paper, 26 new 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides with various substituents in N-aromatic ring were synthesized from commercially available 1,3-benzodioxole in good to excellent yields. All the compounds were elucidated by MS, high resolution (HR)-MS, IR, 1 H-and 13 C-NMR analysis, and evaluated for antifungal activities in vitro against Alternaria alternate, Curvularia lunata and Fusarium oxysporum sp. niveum at 50 µg/mL. Most of the compounds showed higher activities against all the test fungi than their natural model compounds sanguinarine and chelerythrine. For A. alternate and Curvularia lunata, most of them were also more active than thiabendazole, a commercial fungicide standard. The structure-activity relationship indicated that the substituent in N-aromatic ring and its position had significant effect on the activity. The general trend was that halogen atoms and CF 3 remarkably enhanced the activity while CH 3 and OCH 3 decreased the activity. Generally, osubstituted isomers were more active than m-and p-substituted isomer. The present results suggest that the title compounds are potential for the development of new isoquinoline antimicrobial agents.Key words 3,4-dihydroisoquinolinium; 1,2,3,4-tetrahydroisoquinoline; N-heterocyclization; antifungal activity; CuCl 2 -catalyzed oxidative coupling reaction; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidation Alkaloids represent a very extensive group of secondary metabolites with diverse structures, distribution in nature, and biological effects. Natural isoquinolines are one of the largest groups of alkaloids. Among them, there is a relatively small but important class of iminium moiety-containing isoquinoline alkaloids, such as quaternary benzo[c] phenanthridine alkaloids (QBAs), quaternary N-naphthyl isoquinolines, berberines and so on 1,2) (Fig. 1). In the past decades, these compounds have aroused interests of both chemists and pharmacologists for their chemical reactivity and extensive bioactivities including antitumor, [3][4][5] antimicrobial, [6][7][8][9][10][11][12] anti-inflammation, 13) antiplatelet aggregation, 14) anti-angiogenesis, 15) anti-acetylcholinesterase, 16) and antiparasite activities. [17][18][19][20] Our previous studies demonstrated that sanguinarine and chelerythrine ( Fig. 1) might serve as ideal lead compounds to develop new isoquinoline antimicrobial and acaricidal agents. Meanwhile, the iminium moiety (C= N + ) was their determinant for their bioactivities. 11,12,17) The similar cases were also found for antitumor activity of 7-demethyl chelerythrine (NK109) 21) and antibacterial activity of berberine.9) In addition, the molecular planarity was also proven to be an important factor for the activity.21) Based on understanding of the structure-activity relationship above and the aim of developing more potent QBAs-like drugs, we intended to design a cl...

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Section: Resultsmentioning

confidence: 99%

Synthesis and <i>in Vitro</i> Antifungal Activities of New 2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromides

Yang

Yao

Qin

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Due to its high toxicity and insolubility in biological fluids, this compound is not currently used in vivo [16]. Derivatives of fagaronine have been thus synthesized in order to improve their potency as anti-leukemic agents while reducing their toxicity [20,32].…”

Section: Discussionmentioning

confidence: 99%

The anti-invasive activity of synthetic alkaloid ethoxyfagaronine on L1210 leukemia cells is mediated by down-regulation of plasminogen activators and MT1-MMP expression and activity

et al. 2010

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Quaternary benzo[c]phenanthridines such as fagaronine are natural substances which have been reported to exhibit anticancer and anti-leukemic properties. However, the therapeutic use of these molecules is limited due to the high dose required to exhibit anti-tumor activity and subsequent toxicity. In this study, we describe the therapeutic potential of a new derivative of fagaronine, Ethoxyfagaronine (N-methyl-12-ethoxy-2hydroxy-3, 8, 9-trimethoxybenzo[c]-phenanthridiniumchlorhydrate) as an anti-leukemic agent. Cytotoxic activity and cell growth inhibition of Ethoxyfagaronine (Etxfag) was tested on murine L1210 leukemia cells using trypan blue assay and MTT assay. At the concentration of 10(-7) M, Etxfag induced less than 10% of cell death. Etxfag (10(-7) M) was tested on L1210 cell invasiveness using matrigel™ precoated transwell chambers and efficiently reduces the invasive potential of L1210 cells by more than 50% as compared with untreated cells. Western blot and immunofluorescence experiments showed that Etxfag decreased both MT1-MMP expression and activation at the cell surface, decreased plasmin activity by down-regulating u-PAR and uPA expression at the cell surface and increasing PAI-1 secretion in conditioned media. The set of our findings underscore the therapeutic potential of ethoxyfagaronine as a new potential anticancer agent able to prevent leukemic cell dissemination.

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“…high toxicity and insolubility in biological fluids render fagaronine unusable in vivo [31]. In order to improve the anti-leukemic potency while reducing the toxicity of benzo[c]-phenanthridines, derivatives of fagaronine like ethoxfagaronine (etxfag) have been synthesized [20,32]. Etxfag exhibits higher solubility in aqueous solvents and we recently reported that it reduced murine leukemic L1210 cell invasiveness [22].…”

Section: Discussionmentioning

confidence: 99%

“…Adherent cells were incubated with 25 M LY294002 or 25 M LY303511 for 30 min before lysed. Anti-p85 immunoprecipitates were subjected to PI 3-kinase activity determined by PI phosphorylation in the presence of [␥-32 P] ATP. Phosphorylated PI (PIP) was separated by TLC and analysed by autoradiography.…”

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confidence: 99%

Targeting Focal Adhesion Assembly by Ethoxyfagaronine Prevents Lymphoblastic Cell Adhesion to Fibronectin

Ouchania

2012

Analytical Cellular Pathology

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Background: Leukemic cell adhesion to proteins of the bone marrow microenvironment provides signals which control morphology, motility and cell survival. We described herein the ability of ethoxyfagaronine (etxfag), a soluble synthetic derivative of fagaronine, to prevent leukemic cell adhesion to fibronectin peptide (FN/V). Methods: Phosphorylation of fak and pyk2 were evaluated by immunoblotting. Labelled proteins were localized by confocal microscopy. PI 3-kinase activity was evaluated by in vitro kinase assay. Results: Subtoxic concentration of etxfag reduced L1210 cell adhesion to FN/V dependently of β1 integrin engagement. Etxfag impaired FN-dependent formation of β1 clustering without modifying β1 expression at the cell membrane. This was accompanied by a decrease of focal adhesion number, a diminution of fak and pyk2 phosphorylation at Tyr-576, Tyr-861 and Tyr-579, respectively leading to their dissociations from β1 integrin and inhibition of PI 3-kinase activity. Etxfag also induced a cell retraction accompanied by a redistribution of phosphorylated fak and pyk2 in the perinuclear region and lipid raft relocalization. Conclusion: Through its anti-adhesive potential, etxfag, combined with conventional cytotoxic drugs could be potentially designed as a new anti-leukemic drug.

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Synthesis and PC3 androgen-independent prostate cells antiproliferative effect of fagaronine derivatives

Abstract: Fagaronine derivatives syntheses were optimized and their effect on PC3 androgen-independent prostate cell line was evaluated. An assessment of the lipophilicity of the benzo[c ]phenanthridine derivatives was achieved at pH 7.4 and et 6.7 by determining log D.

Cited by 4 publications

References 15 publications

Synthesis and <i>in Vitro</i> Antifungal Activities of New 2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromides

Synthesis and <i>in Vitro</i> Antifungal Activities of New 2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromides

The anti-invasive activity of synthetic alkaloid ethoxyfagaronine on L1210 leukemia cells is mediated by down-regulation of plasminogen activators and MT1-MMP expression and activity

Targeting Focal Adhesion Assembly by Ethoxyfagaronine Prevents Lymphoblastic Cell Adhesion to Fibronectin

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