16 research outputs found
SynthĂšse d'hybrides vinblastine-phomopsine.
La tubuline est une protĂ©ine essentielle de la cellule. En polymĂ©risant sous forme de microtubules, elle crĂ©e notamment le fuseau mitotique le long duquel migrent les chromosomes pendant la mitose. Les mĂ©dicaments qui inhibent la polymĂ©risation et/ou la dĂ©polymĂ©risation de la tubuline sont des composĂ©s majeurs de la thĂ©rapie anticancĂ©reuse. Les vinca-alcaloĂŻdes en sont des reprĂ©sentants importants. Ils induisent la mort des cellules par apoptose, en inhibant la dynamique des microtubules. D autres molĂ©cules d origine naturelle, comme la phomopsine A, se fixent sur la tubuline Ă proximitĂ© ou dans le mĂȘme site de fixation que celui des vinca-alcaloĂŻdes. C est la raison pour laquelle nous avons envisagĂ© d Ă©laborer des composĂ©s antimitotiques hybrides entre la vinblastine et la phomopsine A. Dans ce contexte, deux sĂ©ries de composĂ©s ont Ă©tĂ© conçues. La premiĂšre sĂ©rie d hybrides correspondant Ă des dĂ©rivĂ©s de l anhydrovinblastine fonctionnalisĂ©s en position 7 . Cependant, aucune des trois stratĂ©gies Ă©tudiĂ©es n a permis d accĂ©der Ă ces composĂ©s. La deuxiĂšme sĂ©rie d hybrides, dĂ©rivĂ©s de la 7 -homo-anhydrovinblastine a pu ĂȘtre synthĂ©tisĂ©e grĂące Ă une rĂ©action originale d insertion d acĂ©tylĂšnes activĂ©s au niveau du pont gramine de la vinorelbine, suivie d une rĂ©duction avec un contrĂŽle totale de la rĂ©gio- et stĂ©rĂ©oselectivitĂ©. Dans un premier temps, les rĂ©actions d insertion et de rĂ©duction ont Ă©tĂ© mise au point. Ensuite, deux familles d hybrides portant la chaĂźne latĂ©rale de l octahydrophomopsine en position 8 ou 7 ont Ă©tĂ© synthĂ©tisĂ©s. La plupart des composĂ©s ainsi obtenus possĂ©dent une excellente activitĂ© sur la tubuline et sont trĂšs cytotoxique.Tubulin plays a key role in many cellular functions, like cell division. Microtubules, resulting from its polymerisation, form the mitotic spindle along which chromosomes migrate during mitosis. Tubulin-binding molecules are one of the most important classes of anti-cancer agents with major drugs already on the market and many promising compounds in clinical trials. Vinca-alkaloids are one of these antimitotic drugs inhibiting microtubules dynamics. It was shown that the vinca binding site partially overlaps with that of others natural products, like phomopsin A. In order to explore the vinca domain and to elaborate new acute derivatives, we have elaborated antimitotic vinblastine-phomopsin hybrids. We were interested in the synthesis of two series of hybrids. The first, corresponding to 7 -anhydrovinblastine derivatives could not be obtained. None of the three studied strategies lead to desired compounds. The second series of hybrids, corresponding to functionnalized 7 -homo-anhydrovinblastine derivatives, could be synthetised by an original and regioselective insertion reaction, followed by a stereoselective reduction. Firstly, the isertion reaction was studied using different activated acetylenes. Then, two different families of hybrids were obtained, thanks to the selective insertion of the octahydrophomopsin lateral chain in position 8 or 7 . Almost all the compounds were highly active on tubulin and very cytotoxic.PARIS11-SCD-Bib. Ă©lectronique (914719901) / SudocSudocFranceF
Synthesis of vinblastine-phomopsin hybrids
La tubuline est une protĂ©ine essentielle de la cellule. En polymĂ©risant sous forme de microtubules, elle crĂ©e notamment le fuseau mitotique le long duquel migrent les chromosomes pendant la mitose. Les mĂ©dicaments qui inhibent la polymĂ©risation et/ou la dĂ©polymĂ©risation de la tubuline sont des composĂ©s majeurs de la thĂ©rapie anticancĂ©reuse. Les vinca-alcaloĂŻdes en sont des reprĂ©sentants importants. Ils induisent la mort des cellules par apoptose, en inhibant la dynamique des microtubules. Dâautres molĂ©cules dâorigine naturelle, comme la phomopsine A, se fixent sur la tubuline Ă proximitĂ© ou dans le mĂȘme site de fixation que celui des vinca-alcaloĂŻdes. Câest la raison pour laquelle nous avons envisagĂ© dâĂ©laborer des composĂ©s antimitotiques hybrides entre la vinblastine et la phomopsine A. Dans ce contexte, deux sĂ©ries de composĂ©s ont Ă©tĂ© conçues. La premiĂšre sĂ©rie dâhybrides correspondant Ă des dĂ©rivĂ©s de lâanhydrovinblastine fonctionnalisĂ©s en position 7â. Cependant, aucune des trois stratĂ©gies Ă©tudiĂ©es nâa permis dâaccĂ©der Ă ces composĂ©s. La deuxiĂšme sĂ©rie dâhybrides, dĂ©rivĂ©s de la 7â-homo-anhydrovinblastine a pu ĂȘtre synthĂ©tisĂ©e grĂące Ă une rĂ©action originale dâinsertion dâacĂ©tylĂšnes activĂ©s au niveau du pont gramine de la vinorelbine, suivie dâune rĂ©duction avec un contrĂŽle totale de la rĂ©gio- et stĂ©rĂ©oselectivitĂ©. Dans un premier temps, les rĂ©actions dâinsertion et de rĂ©duction ont Ă©tĂ© mise au point. Ensuite, deux familles dâhybrides portant la chaĂźne latĂ©rale de lâoctahydrophomopsine en position 8â ou 7â ont Ă©tĂ© synthĂ©tisĂ©s. La plupart des composĂ©s ainsi obtenus possĂ©dent une excellente activitĂ© sur la tubuline et sont trĂšs cytotoxique.Tubulin plays a key role in many cellular functions, like cell division. Microtubules, resulting from its polymerisation, form the mitotic spindle along which chromosomes migrate during mitosis. Tubulin-binding molecules are one of the most important classes of anti-cancer agents with major drugs already on the market and many promising compounds in clinical trials. Vinca-alkaloids are one of these antimitotic drugs inhibiting microtubules dynamics. It was shown that the vinca binding site partially overlaps with that of others natural products, like phomopsin A. In order to explore the vinca domain and to elaborate new acute derivatives, we have elaborated antimitotic vinblastine-phomopsin hybrids. We were interested in the synthesis of two series of hybrids. The first, corresponding to 7â-anhydrovinblastine derivatives could not be obtained. None of the three studied strategies lead to desired compounds. The second series of hybrids, corresponding to functionnalized 7â-homo-anhydrovinblastine derivatives, could be synthetised by an original and regioselective insertion reaction, followed by a stereoselective reduction. Firstly, the isertion reaction was studied using different activated acetylenes. Then, two different families of hybrids were obtained, thanks to the selective insertion of the octahydrophomopsin lateral chain in position 8â or 7â. Almost all the compounds were highly active on tubulin and very cytotoxic
SynthĂšse d'hybrides vinblastine-phomopsine
Tubulin plays a key role in many cellular functions, like cell division. Microtubules, resulting from its polymerisation, form the mitotic spindle along which chromosomes migrate during mitosis. Tubulin-binding molecules are one of the most important classes of anti-cancer agents with major drugs already on the market and many promising compounds in clinical trials. Vinca-alkaloids are one of these antimitotic drugs inhibiting microtubules dynamics.It was shown that the vinca binding site partially overlaps with that of others natural products, like phomopsin A. In order to explore the vinca domain and to elaborate new acute derivatives, we have elaborated antimitotic vinblastine-phomopsin hybrids.We were interested in the synthesis of two series of hybrids. The first, corresponding to 7â-anhydrovinblastine derivatives could not be obtained. None of the three studied strategies lead to desired compounds. The second series of hybrids, corresponding to functionnalized 7â-homo-anhydrovinblastine derivatives, could be synthetised by an original and regioselective insertion reaction, followed by a stereoselective reduction. Firstly, the isertion reaction was studied using different activated acetylenes. Then, two different families of hybrids were obtained, thanks to the selective insertion of the octahydrophomopsin lateral chain in position 8â or 7â. Almost all the compounds were highly active on tubulin and very cytotoxic.La tubuline est une protĂ©ine essentielle de la cellule. En polymĂ©risant sous forme de microtubules, elle crĂ©e notamment le fuseau mitotique le long duquel migrent les chromosomes pendant la mitose. Les mĂ©dicaments qui inhibent la polymĂ©risation et/ou la dĂ©polymĂ©risation de la tubuline sont des composĂ©s majeurs de la thĂ©rapie anticancĂ©reuse. Les vinca-alcaloĂŻdes en sont des reprĂ©sentants importants. Ils induisent la mort des cellules par apoptose, en inhibant la dynamique des microtubules. Dâautres molĂ©cules dâorigine naturelle, comme la phomopsine A, se fixent sur la tubuline Ă proximitĂ© ou dans le mĂȘme site de fixation que celui des vinca-alcaloĂŻdes. Câest la raison pour laquelle nous avons envisagĂ© dâĂ©laborer des composĂ©s antimitotiques hybrides entre la vinblastine et la phomopsine A. Dans ce contexte, deux sĂ©ries de composĂ©s ont Ă©tĂ© conçues. La premiĂšre sĂ©rie dâhybrides correspondant Ă des dĂ©rivĂ©s de lâanhydrovinblastine fonctionnalisĂ©s en position 7â. Cependant, aucune des trois stratĂ©gies Ă©tudiĂ©es nâa permis dâaccĂ©der Ă ces composĂ©s.La deuxiĂšme sĂ©rie dâhybrides, dĂ©rivĂ©s de la 7â-homo-anhydrovinblastine a pu ĂȘtre synthĂ©tisĂ©e grĂące Ă une rĂ©action originale dâinsertion dâacĂ©tylĂšnes activĂ©s au niveau du pont gramine de la vinorelbine, suivie dâune rĂ©duction avec un contrĂŽle totale de la rĂ©gio- et stĂ©rĂ©oselectivitĂ©. Dans un premier temps, les rĂ©actions dâinsertion et de rĂ©duction ont Ă©tĂ© mise au point. Ensuite, deux familles dâhybrides portant la chaĂźne latĂ©rale de lâoctahydrophomopsine en position 8â ou 7â ont Ă©tĂ© synthĂ©tisĂ©s. La plupart des composĂ©s ainsi obtenus possĂ©dent une excellente activitĂ© sur la tubuline et sont trĂšs cytotoxique
Discovery and characterization of novel bacterial Carbohydrate Esterases
International audienc
Original Vinca Derivatives: From PâGlycoprotein Substrates to PâGlycoprotein Inhibitors
The first example of vinca derivatives <b>16</b>â<b>18</b> able to modulate P-glycoprotein
(Pgp) efflux activity is
reported. They were elaborated in two steps from vinorelbine <b>3</b> (VLN) by a modification of the velbenamine moiety. These
compounds were able to decrease efficiently Pgp mediated influx and
efflux of rhodamine-123 (Rho) and to restore the cytotoxicity of vinorelbine <b>3</b> (VLN) and doxorubicin (Dox) on K562R (dox-resistant) cell
lines
Original Vinca Derivatives: From PâGlycoprotein Substrates to PâGlycoprotein Inhibitors
The first example of vinca derivatives <b>16</b>â<b>18</b> able to modulate P-glycoprotein
(Pgp) efflux activity is
reported. They were elaborated in two steps from vinorelbine <b>3</b> (VLN) by a modification of the velbenamine moiety. These
compounds were able to decrease efficiently Pgp mediated influx and
efflux of rhodamine-123 (Rho) and to restore the cytotoxicity of vinorelbine <b>3</b> (VLN) and doxorubicin (Dox) on K562R (dox-resistant) cell
lines
Synthesis and biological evaluation of C-13âČ substituted 7âČ-homo-anhydrovinblastine derivatives
International audienc
Regioselective chemo-enzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases
International audienceGenerally, carbohydrate-active enzymes are studied using chromogenic substrates that provide quick and easy color-based detection of enzyme-mediated hydrolysis. In the case of feruloyl esterases, commercially available chromogenic ferulate derivatives are both costly and limited in terms of their experimental application. In this study, we describe solutions for these two issues, using a chemoenzymatic approach to synthesize different ferulate compounds. The overall synthetic routes towards commercially available 5-bromo-4-chloro-3-indolyl and 4-nitrophenyl O-5-feruloyl-α-l-arabinofuranosides 1a and 1b were significantly shortened (7-8 steps reduced to 4-6) and transesterification yields enhanced (from 46 to 73% for 1a and 47 to 86 % for 1b). This was achieved using enzymatic (immobilized Lipolase 100T from Thermomyces lanuginosus) transesterification of unprotected vinyl ferulate to the primary hydroxyl group of αâlâarabinofuranosides. Moreover, a novel feruloylated-butanetriol 4-nitrocatechol-1-yl analog 12, containing a cleavable hydroxylated linker was also synthesized in 29% overall yield in 3 steps (convergent synthesis). The latter route combined regioselective functionalization of 4-nitrocatechol and enzymatic transferuloylation. The use of 12 as a substrate to characterize type A feruloyl esterase from Aspergillus niger reveals the advantages of this substrate for the characterizations of feruloyl esterases
Design of chromogenic probes for identification and evaluation of hetroxylan active enzymes
International audienc
Design of chromogenic probes for efficient screening and evaluation of feruloyl esterase-like activities
International audienc