Synthèses d'analogues indoliques de la famille des aldisines

The family of aldisines, isolated from marine sponges, presents a great interest not only for the synthetic pathways but also for biological aspects. To complete this work, various syntheses of indolic analogues and derivatives of this family were developed. A bibliographic study showing the most known compounds of the aldisines family and their syntheses will be reported in a first part. Then, in a second part, a general and efficicent synthesis of structural analogues of latonduine A was carried out via a palladium-catalysed intramolecular reaction of arylation. Several of these final compounds show a sub-micromolar antiproliferative activity on various tumoral human cell lines. The third part of this work reports the preparation of new 4-hydroxy-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-ones (derivated from the aldisine) from alkyl indole-2-carboxylates. These compounds show a significant activity on Cyclin-Dependent Kinases (CDKs) which is one of the main therapeutic targets for the cancer treatment since the last decade. Finally, a non-classical route to 2,3-diiodoindoles from indole-2-carboxylic acids is described in a fourth part.La famille des aldisines, extraites d éponges marines, présente un intérêt tant du point de vue synthétique que biologique. Dans cette optique, différentes voies de synthèse d analogues et de dérivés indoliques de cette famille ont été développées. Ainsi, dans un premier temps, une étude bibliographique détaillant les composés les plus connus de la famille des aldisines et leurs synthèses a été réalisée. Puis, dans une seconde partie, une synthèse générale et efficace d analogues structuraux de la latonduine A est décrite via une réaction d arylation intramoléculaire pallado-catalysée. Certains des composés préparés possèdent une activité antiproliférative sub-micromolaire sur diverses lignées de cellules tumorales. Une troisième partie de ce travail a permis la préparation de nouvelles 4-hydroxy-2,3,4,5-tétrahydro[1,4]diazépino[1,2-a]indol-1-ones, dérivées de l aldisine, à partir d indole-2-carboxylates d alkyle. Ces composés montrent une activité d inhibition significative des kinases dépendantes des cyclines, cibles thérapeutiques de choix dans le traitement du cancer. Enfin, une nouvelle voie d accès simple et efficace aux 2,3-diiodoindoles a également été découverte à partir d acides indole-2-carboxyliques.LYON1-BU.Sciences (692662101) / SudocSudocFranceF

Synthesis and biological evaluation of tetrahydro[1,4]diazepino[1,2-a]indol-1-ones as cyclin-dependent kinase inhibitors.

International audienceNew series of 2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-ones and 3,4,5,10-tetrahydro-2H-diazepino[3,4-b]indol-1-ones have been synthesized through an iodolactonisation/lactone-to-lactam rearrangement sequence. These compounds were evaluated as potential protein kinase inhibitors (CDK1, CDK5 and GSK-3). 11-Iodo-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one derivatives exhibited sub-micromolar inhibitory activity against cyclin-dependent kinases. Docking studies were realized to determine the binding mode of the inhibitors into the ATP binding domain of the CDK5 catalytic site. Our result highlighted two weak Van-der-Waals bonding interactions established between the iodine atom and both phenyl group of Phe 80 and ammonium end of Lys 33

Synthesis and biological evaluation of tetrahydro[1,4]diazepino[1,2-a]indol-1-ones as cyclin-dependent kinase inhibitors

International audienceNew series of 2,3,4,5-tetrahydro[1,4]diazepino[1,2a]indol-1-ones and 3,4,5,10-tetrahydro-2H-diazepino[3,4-b]indol-1-ones have been synthesized through an iodolactonisation/lactone-to-lactam rearrange-ment sequence. These compounds were evaluated as potential protein kinase inhibitors (CDK1, CDK5 andGSK-3). 11-Iodo-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one derivatives exhibited sub-micromolar inhibitory activity against cyclin-dependent kinases. Docking studies were realized todetermine the binding mode of the inhibitors into the ATP binding domain of the CDK5 catalytic site. Ourresult highlighted two weak Van-der-Waals bonding interactions established between the iodine atomand both phenyl group of Phe 80 and ammonium end of Lys 3

Indolobenzazepin-7-ones and 6-, 8-, and 9-Membered Ring Derivatives as Tubulin Polymerization Inhibitors: Synthesis and Structure−Activity Relationship Studies

Several small weight indole derivatives (D-64131, D-24851, BPR0L075, BLF 61-3, and ATI derivatives) are potent tubulin polymerization inhibitors and show nanomolar antiproliferative activity. Among them, indolobenzazepin-7-ones were recently disclosed as potent antimitotic agents. In an effort to improve this structure, we prepared new derivatives in order to evaluate their antiproliferative activity. 5,6,7,9-Tetrahydro-8H-indolo[2,3-e][3]benzazocin-g-one (1m) was found to be the most potent derivative inhibiting the cell growth of several cancer cell lines in the lower nanomolar range

Synthesis and Reactivity of Oxazinoindolones via Regioselective 6- exo-dig Iodolactonization Reaction

International audienceAn efficient protocol for facile construction of 3,4-dihydro-10-iodo-3-iodomethylene-[1,4]-oxazino[4,3-a]indol-1-ones has been developed by using a regio-and stereoselective iodolactonization reaction. Subsequent palladium cross-coupling reactions of 3,4-dihydro-10-iodo-3-iodomethylene-[1,4]-oxazino[4,3-a]indol-1-ones readily afforded functionalized oxazinoindolones