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1.
Br J Pharmacol ; 180(21): 2736-2749, 2023 11.
Article in English | MEDLINE | ID: mdl-37254803

ABSTRACT

BACKGROUND AND PURPOSE: In macrophages, transient receptor potential vanilloid 2 (TRPV2) channel contributes to various cellular processes such as cytokine production, differentiation, phagocytosis and migration. Due to a lack of selective pharmacological tools, its function in immunological processes is not well understood and the identification of novel and selective TRPV2 modulators is highly desirable. EXPERIMENTAL APPROACH: Novel and selective TRPV2 modulators were identified by screening a compound library using Ca2+ influx assays with human embryonic kidney 293 (HEK293) cells heterologously expressing rat TRPV2. Hits were further characterized and validated with Ca2+ influx and electrophysiological assays. Phagocytosis and migration of macrophages were analysed and the contribution of TRPV2 to the generation of Ca2+ microdomains was studied by total internal reflection fluorescence microscopy (TIRFM). KEY RESULTS: The compound IV2-1, a dithiolane derivative (1,3-dithiolan-2-ylidene)-4-methyl-5-phenylpentan-2-one), is a potent inhibitor of heterologously expressed TRPV2 channels (IC50 = 6.3 ± 0.7 µM) but does not modify TRPV1, TRPV3 or TRPV4 channels. IV2-1 also inhibits TRPV2-mediated Ca2+ influx in macrophages. IV2-1 inhibits macrophage phagocytosis along with valdecoxib and after siRNA-mediated knockdown. Moreover, TRPV2 inhibition inhibits lipopolysaccharide-induced migration of macrophages whereas TRPV2 activation promotes migration. After activation, TRPV2 shapes Ca2+ microdomains predominantly at the margin of macrophages, which are important cellular regions to promote phagocytosis and migration. CONCLUSIONS AND IMPLICATIONS: IV2-1 is a novel TRPV2-selective blocker and underline the role of TRPV2 in macrophage-mediated phagocytosis and migration. Furthermore, we provide evidence that TRPV2 activation generates Ca2+ microdomains, which may be involved in phagocytosis and migration of macrophages.


Subject(s)
Lipopolysaccharides , Macrophages , Humans , Rats , Animals , Lipopolysaccharides/pharmacology , HEK293 Cells , Phagocytosis , Gene Expression , TRPV Cation Channels/genetics
2.
Sci Rep ; 11(1): 20627, 2021 10 18.
Article in English | MEDLINE | ID: mdl-34663887

ABSTRACT

Cnidarians are characterized by the possession of stinging organelles, called nematocysts, which they use for prey capture and defense. Nematocyst discharge is controlled by a mechanosensory apparatus with analogies to vertebrate hair cells. Members of the transient receptor potential (TRPN) ion channel family are supposed to be involved in the transduction of the mechanical stimulus. A small molecule screen was performed to identify compounds that affect nematocyst discharge in Hydra. We identified several [2.2]paracyclophanes that cause inhibition of nematocyst discharge in the low micro-molar range. Further structure-activity analyses within the compound class of [2.2]paracyclophanes showed common features that are required for the inhibitory activity of the [2.2]paracyclophane core motif. This study demonstrates that Hydra can serve as a model for small molecule screens targeting the mechanosensory apparatus in native tissues.


Subject(s)
Hydra/immunology , Nematocyst/drug effects , Nematocyst/physiology , Animals , Biomechanical Phenomena/drug effects , Biomechanical Phenomena/physiology , Cnidaria , Hydra/metabolism , Small Molecule Libraries/pharmacology , Transient Receptor Potential Channels/drug effects , Transient Receptor Potential Channels/physiology
3.
Beilstein J Org Chem ; 14: 515-522, 2018.
Article in English | MEDLINE | ID: mdl-29623112

ABSTRACT

In the presented study, dithi(ol)anylium tetrafluoroborates are added to α,ß-unsaturated ketones in a Michael-type reaction yielding diverse substituted ketene diothi(ol)anes. The reactions proceed at room temperature in 1 or 13 h without the need of further additives. The presented procedure is in particular useful for dithi(ol)anylium tetrafluoroborates without electron-withdrawing groups in α-position. This is advantageous with respect to previous approaches, which were limited to the use of ketene dithioacetals substituted with electron-withdrawing groups. Aiming for the systematic investigation of possible steric and electronic influences on the outcome of the reaction, various combinations of electrophiles and nucleophiles were used and the results of the reactions were compared based on the type of the used dithioacetal. The scope of the presented procedure is shown with four additional transformations including the use of additional electrophiles and nucleophiles, the use of a chiral auxiliary and subsequent reduction of selected products. Additionally, we extended the reaction to the synthesis of diene dithiolanes by addition of an ynone to α-alkyl or aryl-substitued dithiolanylium TFBs.

4.
Org Lett ; 18(15): 3598-601, 2016 08 05.
Article in English | MEDLINE | ID: mdl-27399339

ABSTRACT

A solid supported procedure for the synthesis of benzoxazinones, dihydropyrazinones, quinoxalinones, and dihydrooxazinones using immobilized oxazolones in combination with difunctional nucleophiles as cleavage agent is presented. The scope of the novel method has been demonstrated through subsequent modification of the parent oxazolone scaffold on solid supports using conversions with electrophiles or CuAAC reactions to give functionalized pyrazin-2-ones. The described method allows the synthesis of the target heterocycles in good yields via three to five steps on solid phases with only one chromatographic purification step.

5.
Carcinogenesis ; 34(12): 2804-13, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23975834

ABSTRACT

We have recently demonstrated that the anthocyanidin delphinidin (DEL), one of the most abundant dietary flavonoids, inhibits activation of ErbB and vascular endothelial growth factor receptor family members. These receptors play crucial roles in the context of tumor progression and the outgrowth of blood and lymphatic vessels. Here, we have developed an improved chemical synthesis for DEL in order to study the effects of the aglycon and its degradation product gallic acid (GA) on endothelial and tumor cells in vitro and in vivo. We found that DEL blocked the proliferation in vitro of primary human blood and lymphatic endothelial cells as well as human HT29 colon and rat MT-450 mammary carcinoma cells in a dose-dependent manner. In contrast, its degradation product GA had little effect. At higher concentrations, DEL induced apoptosis of endothelial and tumor cells. Furthermore, DEL potently blocked the outgrowth of lymphatic capillaries in ex vivo lymphangiogenesis assays. In the MT-450 rat syngeneic breast tumor model, it also significantly reduced angiogenesis and tumor-induced lymphangiogenesis when administered in vivo. These data reveal DEL to be a novel antilymphangiogenesis reagent. Surprisingly, however, the application of DEL unexpectedly promoted tumor growth and metastasis in the MT-450 tumor model, suggesting that the antiproliferative effect of DEL on cultured cells does not necessarily reflect the response of tumors to this anthocyanidin in vivo. Furthermore, while DEL may have utility as a cancer chemopreventative agent, its ability to promote tumor growth once a neoplasm develops also needs to be taken into consideration.


Subject(s)
Anthocyanins/pharmacology , Lymphangiogenesis/drug effects , Lymphatic Metastasis/prevention & control , Mammary Neoplasms, Animal/pathology , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , Chemoprevention/methods , Endothelial Cells/drug effects , Endothelial Cells/pathology , HT29 Cells , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/pathology , Humans , Lymphatic Metastasis/genetics , Lymphatic Metastasis/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Phosphorylation/drug effects , Rats , Rats, Wistar , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism
6.
Beilstein J Org Chem ; 8: 1191-9, 2012.
Article in English | MEDLINE | ID: mdl-23019447

ABSTRACT

The synthesis of diverse substituted indole structures on solid supports is described. The immobilization of nitrobenzoic acid onto Merrifield resin and the subsequent treatment with alkenyl Grignard reagents delivered indole carboxylates bound to solid supports. In contrast to results in the liquid phase, ortho,ortho-unsubstituted nitroarenes also delivered indole moieties in good yields. Subsequent palladium-catalyzed reactions (Suzuki, Heck, Sonogashira, Stille) delivered, after cleavage, the desired molecules in moderate to good yields over four steps. The scope and limitations are presented.

7.
Opt Express ; 20(6): 6357-64, 2012 Mar 12.
Article in English | MEDLINE | ID: mdl-22418517

ABSTRACT

The fabrication and characterization of continuously tunable, solution-processed distributed feedback (DFB) lasers in the visible regime is reported. Continuous thin film thickness gradients were achieved by means of horizontal dipping of several conjugated polymer and blended small molecule solutions on cm-scale surface gratings of different periods. We report optically pumped continuously tunable laser emission of 13 nm in the blue, 16 nm in the green and 19 nm in the red spectral region on a single chip respectively. Tuning behavior can be described with the Bragg-equation and the measured thickness profile. The laser threshold is low enough that inexpensive laser diodes can be used as pump sources.


Subject(s)
Lasers, Solid-State , Organic Chemicals/chemistry , Equipment Design , Equipment Failure Analysis , Solutions
8.
Chem Commun (Camb) ; 47(32): 9063-5, 2011 Aug 28.
Article in English | MEDLINE | ID: mdl-21755074

ABSTRACT

A novel access to deuterated and D(3)CO-substituted arenes has been developed using immobilized triazenes as precursors. The linker system and the deuterating cleavage methodology could be shown to be compatible with various functional groups and are therefore suitable for the synthesis of derivatives only hardly available via comparable protocols.


Subject(s)
Deuterium/chemistry , Hydrocarbons, Aromatic/chemical synthesis , Triazenes/chemistry , Carbon Monoxide/chemistry , Deuterium/chemical synthesis , Hydrocarbons, Aromatic/chemistry , Triazenes/chemical synthesis
10.
Chem Commun (Camb) ; (13): 1748-50, 2009 Apr 07.
Article in English | MEDLINE | ID: mdl-19294283

ABSTRACT

Hexaazido and hexaiodo macrocyclic methanofullerenes undergo high-yielding sixfold click reactions or sixfold Heck, Sonogashira and Suzuki cross-coupling reactions, respectively, to yield all organic building blocks for higher molecular architectures.

11.
Chem Commun (Camb) ; (19): 2448-9, 2003 Oct 07.
Article in English | MEDLINE | ID: mdl-14587725

ABSTRACT

Proline-catalysed amination of alpha,alpha-disubstituted racemic aldehydes with azodicarboxylates proceeds smoothly to give configurationally stable scalemic aldehydes and oxazolidinones in up to 86% ee.


Subject(s)
Aldehydes/chemistry , Amines/chemical synthesis , Proline/chemistry , Aldehydes/chemical synthesis , Amination , Aza Compounds/chemistry , Catalysis , Oxazolidinones/chemical synthesis , Stereoisomerism
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