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1.
Chemistry ; 30(29): e202400477, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38498145

ABSTRACT

We present an Ugi multicomponent approach to explore the chemical space around Aspidosperma-type monoterpene indole alkaloids. By variation of the isocyanide and carboxylic acid inputs we demonstrate the rapid generation of molecular diversity and the possibility to introduce handles for further modification. The key Ugi three-component reaction showed full diastereoselectivity towards the cis-fused ring system, which can be rationalized by DFT calculations that moreover indicate that the reaction proceeds via a Passerini-type hydrogen bonding mechanism. Several post-Ugi modifications were also performed, including Pictet-Spengler cyclization to highly complex nonacyclic natural product hybrid scaffolds.

2.
Mol Pharmacol ; 105(4): 301-312, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38346795

ABSTRACT

Atypical chemokine receptor 3 (ACKR3), formerly referred to as CXCR7, is considered to be an interesting drug target. In this study, we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new ACKR3 small-molecule agonist, that will serve as an important new tool to study this ß-arrestin-biased chemokine receptor. VUF15485 binds with nanomolar affinity (pIC50 = 8.3) to human ACKR3, as measured in [125I]CXCL12 competition binding experiments. Moreover, in a bioluminescence resonance energy transfer-based ß-arrestin2 recruitment assay VUF15485 acts as a potent ACKR3 agonist (pEC50 = 7.6) and shows a similar extent of receptor activation compared with CXCL12 when using a newly developed, fluorescence resonance energy transfer-based ACKR3 conformational sensor. Moreover, the ACKR3 agonist VUF15485, tested against a (atypical) chemokine receptor panel (agonist and antagonist mode), proves to be selective for ACKR3. VUF15485 labeled with tritium at one of its methoxy groups ([3H]VUF15485), binds ACKR3 saturably and with high affinity (K d = 8.2 nM). Additionally, [3H]VUF15485 shows rapid binding kinetics and consequently a short residence time (<2 minutes) for binding to ACKR3. The selectivity of [3H]VUF15485 for ACKR3, was confirmed by binding studies, whereupon CXCR3, CXCR4, and ACKR3 small-molecule ligands were competed for binding against the radiolabeled agonist. Interestingly, the chemokine ligands CXCL11 and CXCL12 are not able to displace the binding of [3H]VUF15485 to ACKR3. The radiolabeled VUF15485 was subsequently used to evaluate its binding pocket. Site-directed mutagenesis and docking studies using a recently solved cryo-EM structure propose that VUF15485 binds in the major and the minor binding pocket of ACKR3. SIGNIFICANCE STATEMENT: The atypical chemokine receptor atypical chemokine receptor 3 (ACKR3) is considered an interesting drug target in relation to cancer and multiple sclerosis. The study reports on new chemical biology tools for ACKR3, i.e., a new agonist that can also be radiolabeled and a new ACKR3 conformational sensor, that both can be used to directly study the interaction of ACKR3 ligands with the G protein-coupled receptor.


Subject(s)
Chemokine CXCL12 , Receptors, CXCR4 , Humans , Receptors, CXCR4/metabolism , Chemokine CXCL12/metabolism , Chemokine CXCL11/metabolism , Signal Transduction , Ligands , Binding, Competitive
3.
J Org Chem ; 88(17): 12565-12571, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37607396

ABSTRACT

In the wake of the Covid-19 pandemic, it has become clear that global access to efficacious antiviral drugs will be critical to combat future outbreaks of SARS-CoV-2 or related viruses. The orally available SARS-CoV-2 main protease inhibitor nirmatrelvir has proven an effective treatment option for Covid-19, especially in compromised patients. We report a new synthesis of nirmatrelvir featuring a highly enantioselective biocatalytic desymmetrization (>99% ee) and a highly diastereoselective multicomponent reaction (>25:1 dr) as the key steps. Our route avoids the use of transition metals and peptide coupling reagents, resulting in an overall highly efficient and atom-economic process.


Subject(s)
COVID-19 , Humans , Pandemics , SARS-CoV-2 , Lactams , Leucine , Nitriles
4.
Org Lett ; 25(22): 4005-4009, 2023 Jun 09.
Article in English | MEDLINE | ID: mdl-37224106

ABSTRACT

A cobalt(II) mediated three-component synthesis of 5-substituted-N-sulfonyl-1,3,4-oxadiazol-2(3H)-imines using sulfonyl azides, N-isocyaniminotriphenylphosphorane (NIITP), and carboxylic acids has been developed. This one-pot tandem reaction starts with a nitrene transfer to NIITP, followed by addition of the carboxylic acid to the in situ formed carbodiimide and subsequent intramolecular aza-Wittig reaction. Both the steric constraints of carboxylic acid and the stoichiometry of the employed cobalt salt determine the selectivity toward the two products, i.e. 5-substituted-N-sulfonyl-1,3,4-oxadiazol-2(3H)-imine versus 5-substituted-4-tosyl-2,4-dihydro-3H-1,2,4-triazol-3-one.


Subject(s)
Cobalt , Imines , Carboxylic Acids , Molecular Structure
5.
Anal Chem ; 93(15): 6158-6168, 2021 04 20.
Article in English | MEDLINE | ID: mdl-33832223

ABSTRACT

This study presents, for the first time, the successful application of analyzing a whole gas chromatography (GC) chromatogram by nuclear magnetic resonance (NMR) spectroscopy using a continuous repeatable and stable (n = 280) high-resolution (HR) GC fractionation platform with a 96-well plate. Typically with GC- or liquid chromatography-mass spectrometry analysis, (isomer) standards and/or additional NMR analysis are needed to confirm the identification and/or structure of the analyte of interest. In the case of complex substances (e.g., UVCBs), isomer standards are often unavailable and NMR spectra too complex to achieve this. This proof of concept study shows that a HR GC fractionation collection platform was successfully applied to separate, purify, and enrich isomers in complex substances from a whole GC chromatogram, which would facilitate NMR analysis. As a model substance, a chlorinated paraffin (CP) mixture (>8,000 isomers) was chosen. NMR spectra were obtained from all 96 collected fractions, which provides important information for unravelling their full structure. As a proof of concept, a spectral interpretation of a few NMR spectra was made to assign sub-structures. More research is ongoing for the full characterization of CP isomers using multivariate statistical analysis. For the first time, up to only a few CP isomers per fraction were isolated from a highly complex mixture. These may be further purified and certified as standards, which are urgently needed, and can also be used for persistency, bioaccumulation, or toxicity studies.

6.
Org Lett ; 23(8): 3100-3104, 2021 04 16.
Article in English | MEDLINE | ID: mdl-33787266

ABSTRACT

An unforeseen twist in a seemingly trivial Bischler-Napieralski reaction led to the selective formation of an unexpected carbazole product. The reaction proved to be general, providing access to a range of diversely substituted carbazoles from readily available substrates. Judicious variation of substituents revealed a complex cascade mechanism comprising no less than 10 elementary steps, that could be diverted in multiple ways toward various other carbazole derivatives.

7.
Environ Sci Technol ; 53(24): 14649-14659, 2019 12 17.
Article in English | MEDLINE | ID: mdl-31584268

ABSTRACT

The developing fetus represents a highly sensitive period of exposure to endocrine disrupting compounds (EDCs). However, risk assessment of EDCs is hampered by the lack of data on direct in utero exposure. In this study, we developed a robust analytical methodology for the identification of a wide range of known and unknown EDCs in full-term amniotic fluid (AF). First, a method for extraction and fractionation of a broad range of polar and nonpolar EDCs was developed and validated. Maximal recoveries of reference compounds and minimal interference from the matrix were achieved with a combination of solid phase extraction and dispersive liquid/liquid extraction. Bioassay analysis using cell-based reporter gene assays revealed estrogenic, androgenic, and dioxin-like activity in AF extract corresponding to 1.4 nmol EEQ/L, 76.6 pmol DHT-EQ/L, and 10.1 pmol TEQ/L, respectively. Targeted analysis revealed 13 xenobiotics, phytoestrogens, and endogenous hormones in the AF extract that partly contributed to the bioassay activity. Separation of the complex mixture of chemicals in the AF extract with reversed-phase chromatographic fractionation and subsequent bioassay analysis revealed activity in fractions over a wide range of polarity, indicating diverse (unidentified) substances with potential ED activity. The method developed here represents the first methodological step in an effect-directed analysis approach to identify unknown biologically active compounds in the fetal environment.


Subject(s)
Endocrine Disruptors , Polychlorinated Dibenzodioxins , Water Pollutants, Chemical , Amniotic Fluid , Humans , Solid Phase Extraction
8.
SLAS Technol ; 24(6): 543-555, 2019 12.
Article in English | MEDLINE | ID: mdl-31096846

ABSTRACT

We describe the development of a high-resolution, noncontact fraction collector for liquid chromatography (LC) separations, allowing high-resolution fractionation in high-density well plates. The device is based on a low-dead-volume solenoid valve operated at 1-30 Hz for accurate collection of fractions of equal volume. The solenoid valve was implemented in a modified autosampler resulting in the so-called FractioMate fractionator. The influence of the solenoid supply voltage on solvent release was determined and the effect of the frequency, flow rate, and mobile phase composition was studied. For this purpose, droplet release was visually assessed for a wide range of frequencies and flow rates, followed by quantitative evaluation of a selection of promising settings for highly accurate, repeatable, and stable fraction collection. The potential of the new fraction collector for LC-based bioactivity screening was demonstrated by fractionating the LC eluent of a mixture of estrogenic and androgenic compounds, and a surface water sample (blank and spiked with bioactives) combining mass spectrometric detection and two reporter gene assays for bioactivity detection of the fractions. Additionally, a mixture of two compounds was repeatedly LC separated and fractionated to assess the feasibility of the system for analyte isolation followed by nuclear magnetic resonance analysis.


Subject(s)
Chemical Fractionation/instrumentation , Chromatography, Liquid/instrumentation , Biological Assay , Chromatography, High Pressure Liquid , Genes, Reporter , Humans , MCF-7 Cells , Magnetic Resonance Spectroscopy , Mass Spectrometry , Solvents
9.
Angew Chem Int Ed Engl ; 54(47): 14133-6, 2015 Nov 16.
Article in English | MEDLINE | ID: mdl-26404737

ABSTRACT

The interrupted Fischer indole synthesis of arylhydrazines and biocatalytically generated chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions. We demonstrate that the reaction is compatible with a variety of functional groups. The products are obtained in high optical purity and in reasonable to good yield. We present a plausible reaction mechanism to explain the observed reaction outcome depending on the stoichiometry of the acid mediator. To demonstrate the synthetic utility of our method, pharmaceutically relevant examples of both product classes were synthesized in highly efficient reaction sequences, including a phenserine analogue as a potential cholinesterase inhibitor and constrained tryptamine derivatives as selective inhibitors of the 5-HT6 serotonin receptor and the TRPV1 ion channel.


Subject(s)
Indoles/chemical synthesis , Pyrroles/chemical synthesis , Tryptamines/chemical synthesis , Indoles/chemistry , Molecular Structure , Pyrroles/chemistry , Tryptamines/chemistry
10.
Chemistry ; 21(21): 7808-13, 2015 May 18.
Article in English | MEDLINE | ID: mdl-25868115

ABSTRACT

A practical two-stage one-pot synthesis of N-substituted ß-amino alcohols using aldehydes and isocyanides as starting materials has been developed. This method features mild reaction conditions, broad scope, and general tolerance of functional groups. Based on a less common central carbon-carbon bond disconnection, this protocol complements traditional approaches that involve amines and various carbon electrophiles (epoxides, α-halo ketones, ß-halohydrins). Medicinally relevant products can be prepared in a concise and efficient way from simple building blocks, as demonstrated in the synthesis of the antiasthma drug salbutamol. Upgrading the synthesis to an enantioselective variant is also feasible.


Subject(s)
Albuterol/chemical synthesis , Aldehydes/chemistry , Amino Alcohols/chemical synthesis , Bronchodilator Agents/chemical synthesis , Cyanides/chemistry , Albuterol/chemistry , Aldehydes/chemical synthesis , Amino Alcohols/chemistry , Bronchodilator Agents/chemistry , Combinatorial Chemistry Techniques , Cyanides/chemical synthesis
11.
Org Lett ; 16(19): 5116-9, 2014 Oct 03.
Article in English | MEDLINE | ID: mdl-25229182

ABSTRACT

The reaction of isocyanides with N-tert-butanesulfinimines shows remarkable chemoselectivity. ß-Sulfinylamino isocyanides are formed exclusively with aromatic sulfinimines, while α-sulfeneimino acetamides result when using aliphatic derivatives. A mechanism is suggested for the latter transformation, together with an explanation for the observed selectivity. Finally, a scope study is presented for this remarkably chemoselective reaction.


Subject(s)
Acetamides/chemical synthesis , Cyanides/chemistry , Imines/chemical synthesis , Sulfonium Compounds/chemical synthesis , Acetamides/chemistry , Catalysis , Imines/chemistry , Molecular Structure , Stereoisomerism , Sulfonium Compounds/chemistry
12.
Eur J Med Chem ; 51: 184-92, 2012 May.
Article in English | MEDLINE | ID: mdl-22424612

ABSTRACT

The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the ß-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with pK(i) values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and 30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of ß-arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research.


Subject(s)
Amides/chemistry , Chemistry Techniques, Synthetic , Models, Molecular , Receptors, CXCR/agonists , Styrene/chemistry , Styrene/pharmacology , HEK293 Cells , Humans , Molecular Conformation , Quantitative Structure-Activity Relationship , Styrene/chemical synthesis
13.
Molecules ; 17(2): 1675-85, 2012 Feb 08.
Article in English | MEDLINE | ID: mdl-22318323

ABSTRACT

Non-fused 3,6-dihydro-2H-1,3-thiazine-2-thiones constitute a so far rather unexplored class of compounds, with the latest report dating back more than two decades. Thiazine-2-thiones contain an endocyclic dithiocarbamate group, which is often found in pesticides, in substrates for radical chemistry and in synthetic intermediates towards thioureas and amidines. We now report the multicomponent reaction (MCR) of in situ-generated 1-azadienes with carbon disulfide. With this reaction, a one-step protocol towards the potentially interesting 3,6-dihydro-2H-1,3-thiazine-2-thiones was established and a small library was synthesized.


Subject(s)
Thiazines/chemical synthesis , Thiones/chemical synthesis , Magnetic Resonance Spectroscopy , Mass Spectrometry , Thiazines/chemistry , Thiones/chemistry
14.
Org Biomol Chem ; 10(5): 941-4, 2012 Feb 07.
Article in English | MEDLINE | ID: mdl-22179495

ABSTRACT

An efficient combination of MAO-N-catalyzed desymmetrization of cyclic meso-amines with Ugi-Smiles multicomponent chemistry produced optically pure N-aryl proline amides. This method represents the first report of a fully asymmetric Ugi-Smiles process.


Subject(s)
Amides/chemical synthesis , Proline/chemical synthesis , Amides/chemistry , Amines/chemical synthesis , Amines/chemistry , Catalysis , Cyclization , Models, Molecular , Proline/chemistry , Stereoisomerism
15.
Org Lett ; 13(24): 6496-9, 2011 Dec 16.
Article in English | MEDLINE | ID: mdl-22085248

ABSTRACT

Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by classical methods.


Subject(s)
Nitriles/chemistry , Nitriles/pharmacology , Palladium/chemistry , Phthalazines/chemical synthesis , Catalysis , Molecular Structure , Phthalazines/chemistry , Stereoisomerism
16.
Chemistry ; 17(52): 15039-44, 2011 Dec 23.
Article in English | MEDLINE | ID: mdl-22125085

ABSTRACT

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.

17.
J Am Chem Soc ; 133(14): 5363-71, 2011 Apr 13.
Article in English | MEDLINE | ID: mdl-21322593

ABSTRACT

Optimization of fragment hits toward high-affinity lead compounds is a crucial aspect of fragment-based drug discovery (FBDD). In the current study, we have successfully optimized a fragment by growing into a ligand-inducible subpocket of the binding site of acetylcholine-binding protein (AChBP). This protein is a soluble homologue of the ligand binding domain (LBD) of Cys-loop receptors. The fragment optimization was monitored with X-ray structures of ligand complexes and systematic thermodynamic analyses using surface plasmon resonance (SPR) biosensor analysis and isothermal titration calorimetry (ITC). Using site-directed mutagenesis and AChBP from different species, we find that specific changes in thermodynamic binding profiles, are indicative of interactions with the ligand-inducible subpocket of AChBP. This study illustrates that thermodynamic analysis provides valuable information on ligand binding modes and is complementary to affinity data when guiding rational structure- and fragment-based discovery approaches.


Subject(s)
Carrier Proteins/chemistry , Drug Discovery/methods , Calorimetry , Carrier Proteins/genetics , Carrier Proteins/metabolism , Crystallography, X-Ray , Ligands , Models, Molecular , Mutagenesis, Site-Directed , Protein Conformation/drug effects , Protein Stability/drug effects , Reproducibility of Results , Species Specificity , Surface Plasmon Resonance , Thermodynamics , Tyrosine
18.
Chem Commun (Camb) ; 46(42): 7918-20, 2010 Nov 14.
Article in English | MEDLINE | ID: mdl-20856952

ABSTRACT

A very short and efficient synthesis of the important drug candidate telaprevir, featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps, is presented. The classical issue of lack of stereoselectivity in Ugi- and Passerini-type reactions is circumvented. The atom economic and convergent nature of the synthetic strategy require only very limited use of protective groups.


Subject(s)
Antiviral Agents/chemical synthesis , Oligopeptides/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Biocatalysis , Dimerization , Oxidation-Reduction
19.
Chem Commun (Camb) ; 46(41): 7706-8, 2010 Nov 07.
Article in English | MEDLINE | ID: mdl-20871902

ABSTRACT

We have combined the biocatalytic desymmetrization of 3,4-cis-substituted meso-pyrrolidines with an Ugi-type multicomponent reaction followed in situ by a Pictet-Spengler-type cyclization reaction sequence for the rapid asymmetric synthesis of alkaloid-like polycyclic compounds.


Subject(s)
Alkaloids/biosynthesis , Alkaloids/chemistry , Biocatalysis , Aspergillus niger/enzymology , Cyclization , Monoamine Oxidase/metabolism , Oxidation-Reduction , Stereoisomerism , Substrate Specificity
20.
Eur J Pharmacol ; 632(1-3): 33-8, 2010 Apr 25.
Article in English | MEDLINE | ID: mdl-20138862

ABSTRACT

[(3)H]cimetidine, a radiolabeled histamine H(2) receptor antagonist, binds with high affinity to an unknown hemoprotein in the brain which is not the histamine H(2) receptor. Improgan, a close chemical congener of cimetidine, is a highly effective pain-relieving drug following CNS administration, yet its mechanism of action remains unknown. To test the hypothesis that the [(3)H]cimetidine-binding site is the improgan antinociceptive target, improgan, cimetidine, and 8 other chemical congeners were studied as potential inhibitors of [(3)H]cimetidine binding in membrane fractions from the rat brain. All compounds produced a concentration-dependent inhibition of [(3)H]cimetidine binding over a 500-fold range of potencies (K(i) values were 14.5 to >8000nM). However, antinociceptive potencies in rats did not significantly correlate with [(3)H]cimetidine-binding affinities (r=0.018, p=0.97, n=10). These results suggest that the [(3)H]cimetidine-binding site is not the analgesic target for improgan-like drugs.


Subject(s)
Analgesics/pharmacology , Brain/metabolism , Cimetidine/analogs & derivatives , Cimetidine/antagonists & inhibitors , Analgesics/chemistry , Animals , Binding Sites , Cimetidine/chemistry , Cimetidine/pharmacology , Dose-Response Relationship, Drug , Histamine/metabolism , Histamine H2 Antagonists/metabolism , Male , Molecular Structure , Pain/metabolism , Rats , Rats, Sprague-Dawley
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