4-Nitro-N-phthalyl-l-tryptophan

The crystal structure of the title compound [systematic name: (2R)-3-(1H-indol-3-yl)-2-(4-nitro-1,3-dioxoisoindolin-2-yl)propanoic acid], C19H13N3O6, an analogue of epigenetic modulator RG108, is constrained by strong hydrogen bonds between the indole N—H group and a carbonyl O atom of the phthalimide ring of a symmetry-related mol­ecule, and between the protonated O atom of the carboxyl group and a carbonyl O atom of the phthalimide ring. π–π stacking inter­actions with centroid–centroid distances of 3.638 (1) and 3.610 (1) Å are also observed between indole and phthalimide rings

The dicyclo­hexyl­amine salt of RG108 (N-phthalyl-l-tryptophan), a potential epigenetic modulator

The dicyclo­hexyl­amine salt of RG108 (N-phthalyl-l-tryptophan) co-crystallizes with a water mol­ecule and a disordered mol­ecule of dimethyl­formamide (DMF), viz. dicyclo­hexyl­aminium (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(1H-indol-3-yl)propanoate dimethyl­formamide solvate monohydrate, C12H24N+·C19H13N2O4 −·C3H7NO·H2O. The conformation of the deprotonated compound is constrained by charge-assisted strong hydrogen bonds with the dicyclo­hexyl­aminium ion and a dense hydrogen-bond network involving co-crystallized solvent mol­ecules. The dihedral angle between the fused ring systems in the anion is 58.35 (4)°

Conception, synthèse et évaluation d'inhibiteurs d'ADN méthyltransférases et d'histones désacétylases

The epigenetic mechanisms of regulation have essential roles in carcinogenesis. For example, essential genes for homeostasis as tumour suppressor genes, can be transcriptionally inactivated by aberrant epigenetic changes. These changes are dependent on the activity of several families of enzymes, including histones deacetylases (HDAC) and DNA methyltransferases. These families are both coordinated and interdependent in the gene extinction process. That is why these enzymes may be targets for epigenetic therapies of many cancers. The goal of our work was to inhibit both class of enzyme to obtain antitumour effects responding to the paradigm of re-expression of tumor suppressor genes. We first identified a relatively potent DNA methyltransferase inhibitor on the bacterial DNA methyltransferase model M.HhaI from which we have achieved pharmacomodulations to get compounds with mixed inhibitory activity of DNA methyltransferases and histones deacetylases. These compounds present good anti-cancer activities in vivo. New pharmacomodulations allowed us to get a new series of more active compounds in vitro for inhibition of DNA methyltransferases. From these compounds, we determine a probable mechanism of competition with the cofactor S-Adenosyl-L-Methionine.Les mécanismes de régulations épigénétiques exercent un rôle essentiel dans le processus de cancérogenèse. Par exemple, des gènes essentiels à l’homéostasie, comme les gènes suppresseurs de tumeurs, peuvent être transcriptionnellement inactivés par des modifications épigénétiques aberrantes. Ces modifications sont dépendantes de l’activité de plusieurs familles d’enzymes dont les histones déacétylases (HDAC) et les ADN méthyltransférases (DNMT). Ces familles sont à la fois coordonnées et interdépendantes dans ce processus d’extinction génique. C’est pourquoi ces enzymes peuvent constituer des cibles pour des thérapies épigénétiques de certains cancers. Au cours de nos travaux, nous avons donc cherché à inhiber ces deux classes d'enzymes afin d'obtenir des effets antitumoraux répondant au paradigme de la réexpression des gènes suppresseurs de tumeurs. Nous avons premièrement identifié un inhibiteur d'ADN Méthyltransférase relativement puissant sur l'ADN Méthyltransférase bactérienne modèle M.HhaI à partir duquel nous avons réalisé des pharmacomodulations nous permettant d'obtenir des composés à activité mixte inhibitrice d'ADN Méthyltransférases et d'Histones Désacétylases, lesquels présentent de bonnes activités anticancéreuses in vivo. De nouvelles pharmacomodulations nous ont permis d'obtenir une nouvelle série de composés plus actifs in vitro pour l'inhibition des ADN Méthyltransférases et à partir desquels un mécanisme probable de compétition avec le cofacteur S-Adénosyl-L-Méthionine a pu être mis en évidence.(DOCSC02) -- FUNDP, 201

N-Hydroxy-6-(5-Nitro- Naphtalimide)-Hexanamide Inhibits Lysine Deacetylation, Mitigates Angiogenesis and Reduces Tumor Growth

peer reviewedIn this report, we present a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish). Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA). Finally, ES8 also reduced tumor growth in mouse models of small cell lung cancer. Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies