Synthesis and structure–activity relationship study of cytotoxic germanicane- and lupane-type 3β-O-monodesmosidic saponins starting from betulin

Thibeault, Dominic; Gauthier, Charles; Legault, Jean; Bouchard, Julie; Dufour, Philippe; Pichette, André

doi:10.1016/j.bmc.2007.06.033

Cited by 107 publications

(80 citation statements)

References 72 publications

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“…As previously reported [Gauthier et al, 2006;Thibeault et al, 2007], betulinic acid 3p-O-a-L-rhamnopyranoside (10, IC50 = 2.6-3.9 pM) was the most active monodesmosidic îupane-type saponin of group II against cancer cell lines followed by betulin 3P-0-a-D-mannopyranoside (14,, and betulinic acid 3p-O-a-D-arabinopyranoside (11, IC50 = 10-17 fiM). The saponins (8,9,16) bearing a glucopyranose moiety at either C-3 or C-28 were not able to exhibit cytotoxicity at the maximum concentration tested (IC50 >100 JJM).…”

Section: Haemolysis Of Red Blood Cellssupporting

confidence: 82%

“…As previously reported [Gauthier et al, 2006;Thibeault et al, 2007], betulinic acid 3p-O-a-L-rhamnopyranoside (10, IC50 = 2.6-3.9 pM) was the most active monodesmosidic îupane-type saponin of group II against cancer cell lines followed a glucopyranose moiety at either C-3 or C-28 were not able to exhibit cytotoxicity at the maximum concentration tested (IC50 >100 JJM). Moreover, the unusual a-Larabinofuranosides (5, 6) were also completely inactive against cancer (IC50 >100…”

Section: Haemolysis Of Red Blood Cellssupporting

confidence: 71%

“…While lupane-type saponins tested in this study were almost non-haemolytic, their cytotoxic activity were in some cases superior to oleanane-type saponins and greatly varied according to the nature of the sugar moieties linked to C-3 and C-28 [Gauthier et al, 2006;Thibeault et al, 2007. .…”

Section: Permeabilization Of Cell Membranementioning

confidence: 99%

“…Structure du bevirimat (21), un inhibiteur de la maturation du VIH Nonobstant leur potentiel pharmacologique prometteur , le développement clinique des triterpènes de type lupane est entravé par leur très faible solubilité dans l'eau (0,02 u.g/mL pour 15) [Jâger et al, 2007] et leur coefficient de partition élevé (log P>6) [Thibeault et al, 2007]. Ceci complique la préparation de formulations administrables et diminue grandement leur biodisponibilité dans l'organisme lors d'études in vivo sur animaux [Udeani et ai., 1999].…”

Section: ô » * 21unclassified

“…To this date, more than fifty natural and non-natural saponins have been chemically synthesized such as monodesmosides [Gauthier et al, 2006;Thibeault et al, 2007; and bidesmosides containing various sugar moieties. Our SAR studies have shown that highly potent and/or selective [Gauthier et al, 2006] anticancer agents are obtained for lupane-type saponins bearing an a-L-rhamnopyranose moiety at the C-3 position.…”

Section: Introductionmentioning

confidence: 99%

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Amélioration du comportement biopharmaceutique de triterpènes naturels anticancéreux par synthèse de saponines mono- et bidesmosidiques /

Gauthier¹

2008

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UIUQAC Mise en garde/AdviceAfin de rendre accessible au plus grand nombre le résultat des travaux de recherche menés par ses étudiants gradués et dans l'esprit des règles qui régissent le dépôt et la diffusion des mémoires et thèses produits dans cette Institution, l'Université du Québec à Chicoutimi (UQAC) est fière de rendre accessible une version complète et gratuite de cette oeuvre.Motivated by a desire to make the results of its graduate students' research accessible to all, and in accordance with the rules governing the acceptation and diffusion of dissertations and theses in this Institution, the Université du Québec à Chicoutimi (UQAC) is proud to make a complete version of this work available at no cost to the reader.L'auteur conserve néanmoins la propriété du droit d'auteur qui protège ce mémoire ou cette thèse. Ni le mémoire ou la thèse ni des extraits substantiels de ceux-ci ne peuvent être imprimés ou autrement reproduits sans son autorisation.The author retains ownership of the copyright of this dissertation or thesis. Neither the dissertation or thesis, nor substantial extracts from it, may be printed or otherwise reproduced without the author's permission. "L'imprévisible est dans la nature même de l'entreprise scientifique. Si ce qu 'on va trouver est vraiment nouveau, alors c'est par définition quelque chose d'inconnu à l'avance. "-François Jacob, médecin et biologiste français, prix Nobel de médecine (1965) Ill RESUME Cette thèse décrit les travaux réalisés concernant la synthèse et l'évaluation des activités anticancéreuse et hémolytique de saponines triterpéniques naturelles et nonnatureËes à génine de type lupane. D'une part, deux saponines naturelles à section a-L-rhamnopyranosyl-(l-»2)-a-L-arabinopyranose provenant de plantes de la médecine traditionnelle orientale, une librairie de huit saponines bidesmosidiques à génine bétulinol et acide bétulinique ainsi que plusieurs dérivés chacotriosidiques de type lupane et germanicane ont été préparés par l'utilisation judicieuse de différents groupements protecteurs et procédures de glycosylation. D'autre part, l'étude des relations structure-activité démontre que les sections osidiques hautement polaires à la position C-3 du squelette lupane ont, dans la plupart des cas, un impact négatif sur l'activité anticancéreuse tandis que l'activité est augmentée pour les triterpènes de type germanicane. En revanche, la présence d'une section L-rhamnose à cette position accroît la cytotoxicité des saponines de type lupane. Notablement, le bétulinol 3,28-O-bis-cc-L-rhamnopyranoside s'est révélé un puissant agent anticancéreux inhibant sélectivement la croissance des cellules provenant des cancers les plus prévalents chez l'homme (IC50 = 1,7-1,9 fimol # L"'). À l'inverse des saponines naturelles de type oléanane telles que Pa-hédérine et l'hédéracolchiside Ai, la majorité des saponines de type lupane, tout comme leurs homologues triterpéniques (bétulinol et acide bétulinique), n'induisent pas l'hémolyse des globules rouges (HD50 >100 jurnol'L" 1 ), et c...

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Section: Haemolysis Of Red Blood Cellssupporting

confidence: 82%

“…As previously reported [Gauthier et al, 2006;Thibeault et al, 2007], betulinic acid 3p-O-a-L-rhamnopyranoside (10, IC50 = 2.6-3.9 pM) was the most active monodesmosidic îupane-type saponin of group II against cancer cell lines followed a glucopyranose moiety at either C-3 or C-28 were not able to exhibit cytotoxicity at the maximum concentration tested (IC50 >100 JJM). Moreover, the unusual a-Larabinofuranosides (5, 6) were also completely inactive against cancer (IC50 >100…”

Section: Haemolysis Of Red Blood Cellssupporting

confidence: 71%

Section: Permeabilization Of Cell Membranementioning

confidence: 99%

Section: ô » * 21unclassified

Section: Introductionmentioning

confidence: 99%

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Amélioration du comportement biopharmaceutique de triterpènes naturels anticancéreux par synthèse de saponines mono- et bidesmosidiques /

Gauthier¹

2008

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Synthesis and Anticancer Activity of Novel Betulinic acid and Betulin Derivatives

Kommera

Kaluđerović

Kalbitz

et al. 2010

Archiv der Pharmazie

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A series of novel betulinic acid derivatives 3-11 and betulin derivatives 12-17 were synthesized. The compounds were characterized by the means of (1)H- and (13)C-NMR spectroscopy as well as mass spectrometry. The compounds have been tested on ten tumor cell lines of different histogenic origin. The most active derivatives, containing a chloroacetyl group on C-3 in betulinic acid 9 and C-28 in betulin 15, were up to ten times more cytotoxic and many fold more selective towards tumor cells in comparison to normal cells (fibroblasts) than betulinic acid. Furthermore, compound 15 was found to possess cell growth inhibition even when treated for a short time on anaplastic thyroid cancer cells (SW1736).

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Synthesis of betulin derivatives and the determination of their relative lipophilicities using reversed‐phase thin‐layer chromatography

Achrem-Achremowicz

Kępczyńska

Zylewski

et al. 2009

Biomedical Chromatography

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A series of superlipophilic or highly lipophilic semisynthetic betulin derivatives was prepared and their relative lipophilicity was measured by reversed-phase thin-layer chromatography (RP-TLC) at different pH values using 1,4-dioxane-acetate buffer mixtures as mobile phases. Cholesterol, 17beta-estradiol and pure betulin were used as the reference compounds. Linear relationships were found between R(M) values and 1,4-dioxane concentrations in the mobile phases. LogP values were also calculated with computer programs ACD/LogP (ChemSketch 11.0, Advanced Chemistry Development Inc.) and ClogP (Daylight Chemical Information Systems Inc.). The empirical and theoretical data were compared, and the R(M0) values correlated well with logP. Two of the synthesized betulin derivatives are reported for the first time.

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Synthesis and structure–activity relationship study of cytotoxic germanicane- and lupane-type 3β-O-monodesmosidic saponins starting from betulin

Cited by 107 publications

References 72 publications

Amélioration du comportement biopharmaceutique de triterpènes naturels anticancéreux par synthèse de saponines mono- et bidesmosidiques /

Amélioration du comportement biopharmaceutique de triterpènes naturels anticancéreux par synthèse de saponines mono- et bidesmosidiques /

Synthesis and Anticancer Activity of Novel Betulinic acid and Betulin Derivatives

Synthesis of betulin derivatives and the determination of their relative lipophilicities using reversed‐phase thin‐layer chromatography

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