Réactions domino palladocatalysées, outil efficace pour la synthèse de nouveaux analogues de la combrétastatine A4 à visée antivasculaire

La combrétastatine A4, chef de file des agents antivasculaires, est actuellement en étudeclinique de phase III. Cette molécule d origine naturelle est un puissant inhibiteur de lapolymérisation de la tubuline qui cible in vivo spécifiquement les cellules endothélialestumorales, induisant une obstruction du vaisseau sanguin et la nécrose de la masse tumorale.De nouvelles structures hétérocycliques (oxindole, isochromanone, isoquinoléinone etaroylindole), analogues contraints de la CA4 ont été conçues et synthétisées via des réactionsdomino catalysées par le palladium. Ces composés ont été évalués pour leur capacité à arrondirles cellules EAhy926, à inhiber de polymérisation de la tubuline et leur cytotoxicitéThe antivascular agent combretastatin A4 is currently in a phase III clinical trial. This naturalproduct is a tubulin polymerization inhibitor that rapidly and selectively disrupts abnormaltumour vasculature and causes a vascular shutdown leading to a massive ischemic necrosis ofthe tumour cells.Several new heterocyclic constrained analogues of CA4 (oxindole, isochromanone,isoquinolinone and aroylindole) were considered and synthesized by palladium catalyzeddomino reactions. These compounds were evaluated toward their ability to round up endothelialcells, to inhibit tubulin polymerization. Their cytotoxicities on tumour cells were alsodeterminedPARIS-BIUP (751062107) / SudocSudocFranceF

Tandem Heck-Suzuki-Miyaura reaction: Application to the synthesis of constrained analogues of combretastatin A-4.

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Early Effects of Combretastatin A4 Phosphate Assessed by Anatomic and Carbogen-Based Functional Magnetic Resonance Imaging on Rat Bladder Tumors Implanted in Nude Mice

Combretastatin A4 phosphate (CA4P) causes rapid disruption of the tumor vasculature and is currently being evaluated for antivascular therapy. We describe the initial results obtained with a noninvasive multi-parametric magnetic resonance imaging (MRI) approach to assess the early effects of CA4P on rat bladder tumors implanted on nude mice. MRI (4.7 T) comprised a fast spin-echo sequence for growth curve assessment; a multislice multiecho sequence for T(2) measurement before, 15 minutes after, and 24 hours after CA4P (100 mg/kg); and a fast T(2w)* gradient-echo sequence to assess MR signal modification under carbogen breathing before, 35 minutes after, and 24 hours after CA4P. The tumor fraction with increased T(2w)* signal intensity under carbogen (T(+)) was used to quantify CA4P effect on functional vasculature. CA4P slowed tumor growth over 24 hours and accelerated necrosis development. T(+) decrease was observed already at 35 minutes post-CA4P. Early T(2) increase was observed in regions becoming necrotic at 24 hours post-CA4P, as confirmed by high T(2) and histology. These regions exhibited, under carbogen, a switch from T(2w)* signal increase before CA4P to a decrease post-CA4P. The combination of carbogen-based functional MRI and T(2) measurement may be useful for the early follow-up of antivascular therapy without the administration of contrast agents

Synthesis and biological evaluation of enantiomerically pure cyclopropyl analogues of combretastatin A4

International audienceTo evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (-)-1b, (-)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities

Synthesis and biological evaluation of cis-locked vinylogous combretastatin-A4 analogues: derivatives with a cyclopropyl-vinyl or a cyclopropyl-amide bridge.

International audienceA series of novel combretastatin A4 analogues, in which the cis-olefinic bridge is replaced by a cyclopropyl-vinyl or a cyclopropyl-amide moiety, were synthesized and evaluated for inhibition of tubulin polymerization and antiproliferative activity. The derivative 9a with a (cis,E)-cyclopropyl-vinyl unit is the most promising compound. As expected, molecular docking of 9a has shown that only one of the cis-cyclopropyl enantiomers is a good ligand for tubulin

Synthesis and Structure-Activity Relationships of Constrained Heterocyclic Analogues of Combretastatin A4

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