Richard van den Berg - Academia.edu (original) (raw)

Papers by Richard van den Berg

European Journal of Organic Chemistry, Jun 9, 2015

, [a][ ‡] Elliot D. Mock, [a][ ‡] Anneke Strijland, [b] Wilma E. Donker-Koopman, [b] Hans van den... more , [a][ ‡] Elliot D. Mock, [a][ ‡] Anneke Strijland, [b] Wilma E. Donker-Koopman, [b] Hans van den Elst, [a] Richard J. B. H. N. van den Berg, [a] Johannes M. F. G. Aerts, [a] Gijsbert A. van der Marel, [a] and Herman S. Overkleeft* [a]

Nature Communications, Mar 15, 2023

Cannabinoid CB 2 receptor (CB 2 R) agonists are investigated as therapeutic agents in the clinic.... more Cannabinoid CB 2 receptor (CB 2 R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB 2 R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB 2 R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB 2 R activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB 2 R activation by selective agonists and highlights the role of lipophilicity in CB 2 R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands. Preparations of the plant Cannabis sativa have been used for centuries in the treatment of various diseases, including cancer and neuropathic pain 1. The synthetic version of its psychoactive constituent, Δ 9-tetrahydrocannabinol (THC, Fig. 1), is in FDA approved drugs Marinol® or Syndros® (dronabinol). The extracted version of THC is one of the active constituents of oromucosal spray Sativex® (nabiximols). These drugs are primarily used for the treatment of chemotherapy-induced nausea, enhancement of appetite in cachexic AIDS-patients, and to alleviate the spasticity and pain associated with multiple sclerosis 2-6. However, THC-based therapies are associated with clinically undesired psychotropic and cardiovascular adverse effects and challenging pharmacokinetic properties due to their high lipophilicity that may limit their therapeutic efficacy 7-10. THC exerts its therapeutic effects mostly via the G proteincoupled receptors (GPCRs) cannabinoid CB 1 and CB 2 receptors (CB 1 R and CB 2 R), which have 68% sequence identity in their seven transmembrane (TM) domains 11. Both receptors are activated by the endogenous signaling lipids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) (Fig. 1), the two main endocannabinoids. The CB 1 R, which is the most abundantly expressed GPCR in the central nervous system (CNS) is responsible for the psychotropic side effects of THC 12-14. It plays a role in memory, learning, neurogenesis, neuronal migration, and

European Journal of Organic Chemistry, May 10, 2012

Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Scientific Reports, Nov 6, 2018

Organic & biomolecular chemistry, Jan 25, 2018

Diacylglycerol lipases (DAGL) produce the endocannabinoid 2-arachidonoylglycerol, a key modulator... more Diacylglycerol lipases (DAGL) produce the endocannabinoid 2-arachidonoylglycerol, a key modulator of neurotransmitter release. Chemical tools that visualize endogenous DAGL activity are desired. Here, we report the design, synthesis and application of a triazole urea probe for DAGL equipped with a norbornene as a biorthogonal handle. The activity and selectivity of the probe was assessed with activity-based protein profiling. This probe was potent against endogenous DAGLα (IC50 = 5 nM) and it was successfully applied as a two-step activity-based probe for labeling of DAGLα using an inverse electron-demand Diels-Alder ligation in living cells.

Journal of Organic Chemistry, Jan 23, 2007

In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized ... more In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reported here are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involved in the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decade due to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that an increasing number of pathological processes are being linked to excessive glycosphingolipid levels, glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presented here demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the 1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramide synthase. The beta-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramide synthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketed as treatment for Gaucher disease under the commercial name Zavesca.

Tetrahedron-asymmetry, May 1, 2009

Four dimeric and four monomeric lipophilic iminosugars were synthesized and subsequently evaluate... more Four dimeric and four monomeric lipophilic iminosugars were synthesized and subsequently evaluated on their inhibitory potential towards mammalian glucosylceramide synthase, glucocerebrosidase, β-glucosidase 2, sucrase and lysosomal α-glucosidase. Compared to their monomeric counterparts the dimeric inhibitors showed decreased inhibition of glucosylceramide synthase and generally a comparable inhibitory potency for the glycosidases.

ChemMedChem, Oct 23, 2015

Full Papers Scheme1.Reagents and conditions:a)AcOH, THF/H 2 O, then MsCl,pyridine, À20 8C; b) DMF... more Full Papers Scheme1.Reagents and conditions:a)AcOH, THF/H 2 O, then MsCl,pyridine, À20 8C; b) DMF, K 2 CO 3 ,808C, 72 h; c) LiOH, dioxane/H 2 O, microwave,30min; d) DMF,RT. Figure 2. Structures of the 39-member compound library.

Angewandte Chemie, Oct 27, 2009

Scheme 3. Overview of mammalian (glyco)sphingolipid catabolism. The enzyme/glycosidases and activ... more Scheme 3. Overview of mammalian (glyco)sphingolipid catabolism. The enzyme/glycosidases and activator proteins responsible are indicated at the glycosidic linkage. The associated sphingolipidose (see Section 2) that is manifested by an enzyme defect is also shown.

ACS Medicinal Chemistry Letters, Apr 12, 2011

Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease a... more Glucosylceramide synthase (GCS) is an approved drug target for the treatment of Gaucher disease and is considered as a valid target for combating other human pathologies, including type 2 diabetes. The clinical drug N-butyldeoxynojirimycin (Zavesca) is thought to inhibit through mimicry of its substrate, ceramide. In this work we demonstrate that, in contrast to what is proposed in this model, the C2-hydroxyl of the deoxynojirimycin core is important for GCS inhibition. Here we show that C6-OH appears of less important, which may set guidelines for the development of GCS inhibitors that have less affinity (in comparison with Zavesca) for other glycoprocessing enzymes, in particular those hydrolases that act on glucosylceramide.

Chemistry, an Asian journal, Jan 14, 2018

Diacylglycerol lipases (DAGL) are responsible for the biosynthesis of the endocannabinoid 2-arach... more Diacylglycerol lipases (DAGL) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol. The fluorescent activity-based probes DH379 and HT-01 have been previously shown to label DAGLs and to cross-react with the serine hydrolase ABHD6. Here, we report the synthesis and characterization of two new quenched activity-based probes 1 and 2, the design of which was based on the structures of DH379 and HT-01, respectively. Probe 1 contains a BODIPY-FL and a 2,4-dinitroaniline moiety as a fluorophore-quencher pair, whereas probe 2 employs a Cy5-fluorophore and a cAB40-quencher. The fluorescence of both probes was quenched with relative quantum yields of 0.34 and 0.0081, respectively. The probes showed target inhibition as characterized in activity-based protein profiling assays using human cell- and mouse brain lysates, but were unfortunately not active in living cells, presumably due to limited cell permeability.

Journal of Medicinal Chemistry, 2014

This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their... more This work details the evaluation of a number of N-alkylated deoxynojirimycin derivatives on their merits as dual glucosylceramide synthase/neutral glucosylceramidase inhibitors. Building on our previous work, we synthesized a series of D-gluco and L-ido-configured iminosugars N-modified with a variety of hydrophobic functional groups. We found that iminosugars featuring N-pentyloxymethylaryl substituents are considerably more potent inhibitors of glucosylceramide synthase than their aliphatic counterparts. In a next optimization round, we explored a series of biphenyl-substituted iminosugars of both configurations (D-gluco and L-ido) with the aim to introduce structural features known to confer metabolic stability to drug-like molecules. From these series, two sets of molecules emerge as lead series for further profiling. Biphenyl-substituted L-ido-configured deoxynojirimycin derivatives are selective for glucosylceramidase and the nonlysosomal glucosylceramidase, and we consider these as leads for the treatment of neuropathological lysosomal storage disorders. Their D-gluco-counterparts are also potent inhibitors of intestinal glycosidases, and because of this characteristic, we regard these as the prime candidates for type 2 diabetes therapeutics.

Lab on a Chip, 2012

All chemicals were acquired from Sigma-Aldrich Co. (Zwijndrecht, The Netherlands), unless noted o... more All chemicals were acquired from Sigma-Aldrich Co. (Zwijndrecht, The Netherlands), unless noted otherwise. Labeling of glutamic acid, phenyl alanine, and leucine with fluorescein isothiocyanate (FITC) was performed as follows. To 0.5 mmol of amino acid an aqueous solution of potassium hydroxide, 1 g/ml, was added in a ratio of 1:1 (weight:volume), followed by addition of 1 ml of ethanol. Under vigorous stirring, on ice, a suspension of FITC, 1 mol/L in ethanol was added to the amino acid 1:1 (mol:mol) together with 1 ml 0.5 mol/L potassium hydroxide and 0.5 mL ethanol. This mixture was left on ice to react for 2 h in the dark under continued stirring. Purification of the reaction product was performed using a Gilson preparative HPLC system (Gilson, Inc., Middleton, USA) equipped with a Phenomex Gemini C18 column, 15x21 mm, 5 micron (Phenomenex, Torrance, USA) using an acetonitrile/water (10 mmol/L ammonium acetate, pH = 8) gradient. Purity of compounds was established with LC-UV-MS and CZE-LIF and found to be >99%. After freeze-drying, each purified FITC-amino was dissolved in dimethyl sulfoxide (DMSO), 1 mmol/L, and stored at-80 • C awaiting experiments. FITC, having a pKa of 6.7 1 , fluoresces strongly when negatively charged at valence-2. FITC labeled biosamples are of general interest. FITC-labeled amino acids have been studied with CZE 2-4 chip ZE 5,6 and ITP in capillary 7-9 , and in microchannels 10 and other techniques 11. As unpurified reaction product is used almost exclusively in these publications, the two most abundant fluorescent by-products of this labeling are considered to be of interest and were purified and identified

European Journal of Organic Chemistry, 2015

, [a][ ‡] Henrik Gold, [a][ ‡] Mina Mirzaian, [b] Maria J. Ferraz, [b] Ginger Lutteke, [a] Richar... more , [a][ ‡] Henrik Gold, [a][ ‡] Mina Mirzaian, [b] Maria J. Ferraz, [b] Ginger Lutteke, [a] Richard J. B. H. N. van den Berg, [a] Hans van den Elst, [a] Johan Lugtenburg, [a] Gijsbert A. van der Marel, [a] Johannes M. F. G. Aerts, [a,b] Jeroen D. C. Codée,* [a] and Herman S. Overkleeft* [a]

Journal of Lipid Research

European Journal of Organic Chemistry

License: Article 25fa pilot End User Agreement This publication is distributed under the terms of... more License: Article 25fa pilot End User Agreement This publication is distributed under the terms of Article 25fa of the Dutch Copyright Act (Auteurswet) with explicit consent by the author. Dutch law entitles the maker of a short scientific work funded either wholly or partially by Dutch public funds to make that work publicly available for no consideration following a reasonable period of time after the work was first published, provided that clear reference is made to the source of the first publication of the work. This publication is distributed under The Association of Universities in the Netherlands (VSNU) 'Article 25fa implementation' pilot project. In this pilot research outputs of researchers employed by Dutch Universities that comply with the legal requirements of Article 25fa of the Dutch Copyright Act are distributed online and free of cost or other barriers in institutional repositories. Research outputs are distributed six months after their first online publication in the original published version and with proper attribution to the source of the original publication. You are permitted to download and use the publication for personal purposes. All rights remain with the author(s) and/or copyrights owner(s) of this work. Any use of the publication other than authorised under this licence or copyright law is prohibited. If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons.

$Research paper thumbnail of {"__content__"=>"Development of a Cannabinoid-Based Photoaffinity Probe to Determine the Δ-Tetrahydrocannabinol Protein Interaction Landscape in Neuroblastoma Cells.", "sup"=>{"__content__"=>"8/9"}}$

Cannabis and cannabinoid research, 2018

Δ-Tetrahydrocannabinol (THC), the principle psychoactive ingredient in , is widely used for its t... more Δ-Tetrahydrocannabinol (THC), the principle psychoactive ingredient in , is widely used for its therapeutic effects in a large variety of diseases, but it also has numerous neurological side effects. The cannabinoid receptors (CBRs) are responsible to a large extent for these, but not all biological responses are mediated via the CBRs. The identification of additional target proteins of THC to enable a better understanding of the (adverse) physiological effects of THC. In this study, a chemical proteomics approach using a two-step photoaffinity probe is applied to identify potential proteins that may interact with THC. Photoaffinity probe , containing a diazirine as a photocrosslinker, and a terminal alkyne as a ligation handle, was synthesized in 14 steps. It demonstrated high affinity for both CBRs. Subsequently, two-step photoaffinity labeling in neuroblastoma cells led to identification of four potential novel protein targets of THC. The identification of these putative protein ...

Journal of the American Chemical Society

Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of gl... more Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.

Med. Chem. Commun., 2017

The enantioselective synthesis and structure–activity relationships of deoxy-iminosugar-based tri... more The enantioselective synthesis and structure–activity relationships of deoxy-iminosugar-based triazole ureas as dual inhibitors of DAGLα and ABHD6 were reported.