Nicolas Gaboriaud-Kolar

Novel Inverse Binding Mode of Indirubin Derivatives Yields Improved Selectivity for DYRK Kinases

DYRK kinases are involved in alternative pre-mRNA splicing as well as in neuropathological states such as Alzheimers disease and Down syndrome. In this study, we present the design, synthesis, and biological evaluation of indirubins as DYRK inhibitors with enhanced selectivity. Modifications of the bis-indole included polar or acidic functionalities at positions 5′ and 6′ and a bromine or a trifluoromethyl group at position 7, affording analogues that possess high activity and pronounced specificity. Compound 6i carrying a 5′-carboxylate moiety demonstrated the best inhibitory profile. A novel inverse binding mode, which forms the basis for the improved selectivity, was suggested by molecular modeling and confirmed by determining the crystal structure of DYRK2 in complex with 6i. Structure–activity relationships were further established, including a thermodynamic analysis of binding site water molecules, offering a structural explanation for the selective DYRK inhibition.

Indirubin Core Structure of Glycogen Synthase Kinase-3 Inhibitors as Novel Chemotype for Intervention with 5-Lipoxygenase

The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 μM), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.

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.

Oxidative Burst Inhibitory and Cytotoxic Indoloquinazoline and Furoquinoline Alkaloids from Oricia suaveolens

Two new β-indoloquinazoline alkaloids, orisuaveoline A (1) and orisuaveoline B (2), two new furoquinoline alkaloids, quinosuaveoline A (5) and quinosuaveoline B (6), and 12 known compounds were isolated from Oricia suaveolens. The structures of the new compounds were deduced by spectroscopic studies. The absolute configuration of nkolbisine (4) was also determined. Compounds 2, 3, 6-8, 10, and 14 were evaluated for oxidative burst inhibitory activity in a chemoluminescence assay and for cytotoxicity against A549 lung carcinoma cells.

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).

From drug screening to target deconvolution: A target-based drug discovery pipeline using Leishmania casein kinase 1 isoform 2 to identify compounds with anti-leishmanial activity.

ABSTRACT Existing therapies for leishmaniases present significant limitations, such as toxic side effects, and are rendered inefficient by parasite resistance. It is of utmost importance to develop novel drugs targeting Leishmania that take these two limitations into consideration. We thus chose a target-based approach using an exoprotein kinase, Leishmania casein kinase 1.2 (LmCK1.2) that was recently shown to be essential for intracellular parasite survival and infectivity. We developed a four-step pipeline to identify novel selective antileishmanial compounds. In step 1, we screened 5,018 compounds from kinase-biased libraries with Leishmania and mammalian CK1 in order to identify hit compounds and assess their specificity. For step 2, we selected 88 compounds among those with the lowest 50% inhibitory concentration to test their biological activity on host-free parasites using a resazurin reduction assay and on intramacrophagic amastigotes using a high content phenotypic assay. Only 75 compounds showed antileishmanial activity and were retained for step 3 to evaluate their toxicity against mouse macrophages and human cell lines. The four compounds that displayed a selectivity index above 10 were then assessed for their affinity to LmCK1.2 using a target deconvolution strategy in step 4. Finally, we retained two compounds, PP2 and compound 42, for which LmCK1.2 seems to be the primary target. Using this four-step pipeline, we identify from several thousand molecules, two lead compounds with a selective antileishmanial activity.

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.

A Colorful History: The Evolution of Indigoids

Indigo and Tyrian purple are two dyes that have been used historically worldwide, with their colors due mainly to the presence of indigoids. Indigoids are a fascinating class of natural products that are found in several plants and in marine organisms. This small family of natural products is composed of 13 members, with indigo being the most well-known and the main component of Indigo dyes. Their chemical structures rely on the connectivity of two indole moieties. Although there is a limited number of indigoids, they represent one of the oldest natural compound classes used by mankind and their chemical development and importance are intimately linked with the development of human society and the rise of the industrial revolution in the nineteenth century.

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.

(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.