(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

Biomimetic Synthesis of Oleocanthal, Oleacein, and Their Analogues Starting from Oleuropein, A Major Compound of Olive Leaves

Oleocanthal and oleacein are known for a wide range of beneficial activities in human health and the prevention of diseases. The inability to isolate significant and pure amounts of these natural compounds and their demanding synthesis lead to the development of an efficient, five-step, three-pot procedure. The synthesis is performed by a convenient biomimetic approach, starting from oleuropein, an abundant raw material in olive leaves, through the mixed anhydride of oleoside. The method is stereocontrolled and provides an efficient approach to the synthesis of various oleocanthal analogues; thus, a small library of four compounds was prepared with 35-45% overall yield. © 2020 American Chemical Society and American Society of Pharmacognosy

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

Natural-based indirubins display potent cytotoxicity toward wild-type and T315I-resistant leukemia cell lines

Drug resistance in chronic myelogenous leukemia (CML) requires the development of new CML chemotherapeutic drugs. Indirubin, a well-known mutikinase inhibitor, is the major active component of "Danggui Longhui Wan", a Chinese traditional medicine used for the treatment of CML symptoms. An in-house collection of indirubin derivatives was screened at 1 μM on wild-type and imatinib-resistant T315I mutant CML cells. Herein are reported that only 15 analogues of the natural 6-bromoindirubin displayed potent cytotoxicity in the submicromolar range. Kinase assays in vitro show that eight out of the 15 active molecules strongly inhibited both c-Src and Abl oncogenic kinases in the nanomolar range. Most importantly, these eight molecules blocked the activity of T315I mutant Abl kinase at the submicromolar level and with analogue 22 exhibiting inhibitory activity at the low nanomolar range. Docking calculations suggested that active indirubins might inhibit T315I Abl kinase through an unprecedented binding to both active and Src-like inactive conformations. Analogue 22 is the first derivative of a natural product identified as an inhibitor of wild-type and imatinib-resistant T315I mutant Abl kinases. © 2016 The American Chemical Society and American Society of Pharmacognosy

Indirubin derivatives are potent and selective anti-Trypanosoma cruzi agents

Current treatment for combatting Chagas disease, a life-threatening illness caused by the kinetoplastid protozoan parasite Trypanosoma cruzi is inadequate, and thus the discovery of new antiparasitic compounds is of prime importance. Previous studies identified the indirubins, a class of ATP kinase inhibitors, as potent growth inhibitors of the related kinetoplastid Leishmania. Herein, we evaluated the inhibitory activity of a series of 69 indirubin analogues screened against T. cruzi trypomastigotes and intracellular amastigotes. Seven indirubins were identified as potent T. cruzi inhibitors (low µ?, nM range). Cell death analysis of specific compounds [3‘oxime-6-bromoindirubin (6-BIO) analogues 10, 11 and 17, bearing a bulky extension on the oxime moiety and one 7 substituted analogue 32], as evaluated by electron microscopy and flow cytometry, showed a different mode of action between compound 32 compared to the three 6-BIO oxime- substituted indirubins, suggesting that indirubins may kill the parasite by different mechanisms dependent on their substitution. Moreover, the efficacy of four compounds that show the most potent antiparasitic effect in both trypomastigotes and intracellular amastigotes (10, 11, 17, 32), was evaluated in a mouse model of T. cruzi infection. Compound 11 (3‘piperazine-6-BIO) displayed the best in vivo efficacy (1/6 mortality, 94.5% blood parasitaemia reduction, 12 dpi) at a dose five times reduced over the reference drug benznidazole (20 mg/kg vs100 mg/kg). We propose 3‘piperazine-6-BIO as a potential lead for the development of new treatments of Chagas disease. © 2018 The Author(s)

Indirubin derivatives are potent and selective anti-Trypanosoma cruzi agents

Current treatment for combatting Chagas disease, a life-threatening illness caused by the kinetoplastid protozoan parasite Trypanosoma cruzi is inadequate, and thus the discovery of new antiparasitic compounds is of prime importance. Previous studies identified the indirubins, a class of ATP kinase inhibitors, as potent growth inhibitors of the related kinetoplastid Leishmania. Herein, we evaluated the inhibitory activity of a series of 69 indirubin analogues screened against T. cruzi trypomastigotes and intracellular amastigotes. Seven indirubins were identified as potent T. cruzi inhibitors (low µ?, nM range). Cell death analysis of specific compounds [3‘oxime-6-bromoindirubin (6-BIO) analogues 10, 11 and 17, bearing a bulky extension on the oxime moiety and one 7 substituted analogue 32], as evaluated by electron microscopy and flow cytometry, showed a different mode of action between compound 32 compared to the three 6-BIO oxime- substituted indirubins, suggesting that indirubins may kill the parasite by different mechanisms dependent on their substitution. Moreover, the efficacy of four compounds that show the most potent antiparasitic effect in both trypomastigotes and intracellular amastigotes (10, 11, 17, 32), was evaluated in a mouse model of T. cruzi infection. Compound 11 (3‘piperazine-6-BIO) displayed the best in vivo efficacy (1/6 mortality, 94.5% blood parasitaemia reduction, 12 dpi) at a dose five times reduced over the reference drug benznidazole (20 mg/kg vs100 mg/kg). We propose 3‘piperazine-6-BIO as a potential lead for the development of new treatments of Chagas disease. © 2018 The Author(s)