Discovery and optimization of a selective ligand for the switch/sucrose nonfermenting-related bromodomains of polybromo protein-1 by the use of virtual screening and hydration analysis

Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein−ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5)

Conception, synthèse et évaluation biologique de nouveaux dérivés de l'acronycine à potentialité antitumorale

L objet de ce travail est l obtention de nouveaux dérivés de l acronycine, alcaloïde naturel. Deux séries ont été développées. La première a abouti à l obtention d un nouveau composé en série acronycine, la triazoloacronycine, ainsi que plusieurs intermédiaires potentiellement intéressants. La deuxième série développée aura permis la synthèse de nouveaux analogues de la psorospermine, furanoxanthone naturelle, en série benzo[b]acronycine. Pour cela, une méthode mettant en jeu des micro-organismes a notamment été mise au point. L'activité cytotoxique des composés préparés a été évaluée in vitro sur des modèles de leucémies murines L1210 et de tumeurs solides KB-3-1. La triazoloacronycine s est révélée être quatre fois plus active que le composé naturel. Les analogues de la psorospermine également développés, possèdent des activités de l ordre du nanomolaire et ont fait l objet d une étude approfondie de leur mécanisme d action in vitro. Ce sont des alkylants de l ADN ciblant le grand sillon.The aim of this work is the preparation of natural occuring alcaloïd acronycine new derivatives. Two series were developped. The first one led to the synthesis of the triazoloacronycine new compound in acronycine series and of some interesting intermediates. The second one led to the synthesis of new psorospermin naturally occuring furanoxanthone. analogs in the benzo[b]acronycine series. For this, a new method involving micro-organism has been developped. The cytotoxic activity of the prepared compounds was evaluated on murine leukemic L1210 and human carcinoma KB-3-1 cells in vitro. Triazoloacronycine compound is four time more active than the naturaly occuring alcaloid. The psorospermin-acronycine analogs have a nanomolar activity and their mechanism of action was deeply studied. Those compounds are DNA alkylating agents targetting the major groovePARIS-BIUP (751062107) / SudocSudocFranceF

(WO2011057959) Indole and indazole derivatives as glycogen synthase activators: A patent evaluation

Scientific evaluation of a patent aiming for the development of indole and indazole derivatives from biaryloxymethylarene as glycogen synthase activators, a key enzyme involved in type 2 diabetes mellitus. © 2011 Informa UK, Ltd

Glycogen phosphorylase inhibitors: A patent review (2008-2012)

Introduction: Glycogen phosphorylase (GP) is the enzyme responsible for the synthesis of glucose-1-phosphate, the source of energy for muscles and the rest of the body. The binding of different ligands in catalytic or allosteric sites assures activation and deactivation of the enzyme. A description of the regulation mechanism and the implications in glycogen metabolism are given. Areas covered: Deregulation of GP has been observed in diseases such as diabetes mellitus or cancers. Therefore, it appears as an attractive therapeutic target for the treatment of such pathologies. Numbers of inhibitors have been published in academic literature or patented in the last two decades. This review presents the main patent claims published between 2008 and 2012. Expert opinion: Good inhibitors with interesting IC50 and in vivo results are presented. However, such therapeutic strategy raises questions and some answers are proposed to bring new insights in the field. © 2013 Informa UK, Ltd

Indirubin derivatives: A patent review (2010-present)

Introduction: Indirubins are bisindole alkaloids naturally occurring in indigo-bearing plants or in mollusks from the Muricidae family. They belong to the rather small family of indigoids, which has nevertheless found an extreme importance in the fields of dyes and medicinal chemistry. Indirubin has been found to be the active ingredient of a traditional Chinese Medicine used to treat the symptoms of leukemia. Further biological explorations revealed the ability of indirubin to bind cyclin-dependent kinases and 6-bromoindirubin, extracted from mollusks, to bind glycogen synthase kinase-3. The high affinity displayed by the two natural products has opened a vast field of research and triggered the development of hundred of derivatives with biological activities.Areas covered: The traditional use of indirubin for the treatment of leukemia has prompted different research groups to study the cytotoxic effect of indirubin derivatives on both solid tumors and leukemia. Moreover, the affinity of indirubins for kinases also allowed the exploration of their activity towards stem cells.Expert opinion: The derivatives presented are in accordance with first discoveries and establish the close relation between activity and kinase inhibition. New derivatives have been patented and new interferences in signaling pathways are described. However, few in vivo studies have been performed and more efficient solutions are needed to unravel the major issue of solubility. © 2015 Informa UK, Ltd

Symphonia globulifera, a widespread source of complex metabolites with potent biological activities

Symphonia globulifera has been widely used in traditional medicine and has therefore been subjected to several phytochemical studies in the American and African continents. Interestingly, some disparities have been observed concerning its metabolic profile. Several phytochemical studies of S. globulifera have led to the identification of more than 40 compounds, including several polycyclic polyprenylated acylphloroglucinols. Biological evaluations have pointed out the promising biological activities of these secondary metabolites, mostly as antiparasitic or antimicrobial, confirming the traditional use of this plant. The purpose of this review is to describe the natural occurrence, botanical aspects, ethnomedicinal use, structure, and biogenesis, as well as biological activities of compounds isolated from this species according to their provenance. © Georg Thieme Verlag KG Stuttgart.New York