Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis,including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones

Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents.     

Substituierte N,N′-Bis(thiazol-2-yl)-diaminoalkane aus α-Thiocyanato-acetophenonen und N,N′-Dialkyl-diamino-alkanen

Substituted N,N′-Bis(thiazol-2-yl)-diaminoalkanes from α-Thiocyanato-acetophenones and N,N′-Dialkyl-diaminoalkanes α-Thiocyanato-acetophenones 1 react with N,N′-dialkyl-diaminoalkanes 2 in the presence of an appropriate weak acid (acetic acid, propionic acid, benzoic acid) to give the hitherto unknown N,N′-dialkyl-N,N′-bis(4-aryl-thiazol-2-yl)-diaminoalkanes 3 . As reaction medium aliphatic alcohols (ethanol, methanol), halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride) or dipolar-aprotic solvents (acetonitrile, dimethylformamide) can be used. - I.r., u.v., n.m.r. and mass spectroscopic data of the novel bisthiazoles 3 are reported.     

Synthese neuer Thieno [2′,3′; 4,5]imidazo[1,2-a]pyridiniumsalze

Syntheses of New Salts of Thieno[2′,3′;4,5]imidazo[1,2-a]pyridines Mesomeric 1-[2-amino-1-cyano-2-thio-]ethene-pyridinium ylides 1 are cyclizized to imidazo[1,2-a]pyridinium ylides 2 in the presence of HgO. S-alkylation of 2 leads to derivatives of 1-R¹-2-thio-3-cyano-imidazo[1,2-a]pyridinium halides 3 or 4 . Alkylation products from 2 with α-haloketones are cyclizized to thieno[2′,3′ 4,5]imidazo[1,2-a]pyridinium salts 5 .     

Influence of the alkyl-chain size on the amphiphilic behaviour of poly(3-alkyl-1-vinylimidazolium) bromide in aqueous medium

Summary Several 3-alkyl-1-vinylimidazolium bromides differing by the length of the alkyl chain were prepared and polymerized using a free radical route. The behaviour of the obtained homopolymers in aqueous medium was investigated by several physico-chemical methods including viscosimetry, surface tension measurements and fluorescence spectroscopy. These experiments highlighted a strong influence of the length of the pendent alkyl chain on the side-chain aggregation tendency which is a property of such amphiphilic comb polymers. Fluorescence experiments were also conducted on the surface active analogues, in order to compare their behaviour to that of the polymers. Received: 28 June 2000/Revised version: 28 November 2000/Accepted: 20 December 2000     

Morphology of wax modified coil coatings without and with pigmentation

Wax modified coil coatings without and with white pigmentation were analyzed by optical light microscopy, Raman spectroscopy and Atomic Force Microscopy. By optical light and Raman microscopy dispersed spherical wax domains in the micrometer range were ascertained on the surface and within the bulk of the coatings. By the combined Atomic Force microscopical and Raman spectroscopical approach it was possible to detect resin and pigment residues in the lubricant features with diameters above 2 μm. Vice versa indications for wax inclusions with diameters below 2 μm in the matrix and rather thin wax layers expanding from the spherical lubricant domains onto the surface were obtained. As to the wax distribution evaluated by optical light and Raman microscopy significant differences between clearcoat and white topcoat were detected. The non-pigmented coating exhibited smaller wax features and an inhomogeneous distribution with less wax on the surface.     

Pyryliumverbindungen. 38. Zur Ringtransformation von 2,4,6-Triaryl-thiopyryliumsalzen mit Essigsäureanhydrid zu Arylbenzenen und Thiobenzophenonen

Pyrylium Compounds. 38. About the Ring Transformation of 2,4,6-Triarylthiopyrylium Salts by Acetic Acid Anhydride to Arylbenzenes and Thiobenzophenones 2,4,6-Triarylthiopyrylium salts 5 react in the presence of an appropriate condensing agent (sodium acetate, carbonate, methoxide, tert-butoxide or potassium acetate) with acetic acid anhydride to yield arylbenzenes 3 and thiobenzophenones 6 . This ring transformation represents the first example of the conversion of the moiety into the thiocarbonyl group Under the same conditions 3,5-dimethyl-2,4,6-triphenylthiopyrylium perchlorate ( 13 ) forms via [1,5]-sigmatropic rearrangement the thiobenzophenone 15 . The structure of the new compounds 6 was proved by spectroscopic methods as well as by degradation reactions. Thus, hydrogen peroxide converts 6a to the known benzophenone 4 . Alkaline saponification gives the 2-hydroxy-benzophenone 8 , whereas heating with hydrochloric acid causes a selective cleavage of the acetoxy group to the 2-hydroxy-thiobenzophenone 7 .     

Tetrazolverbindungen. 1. 1-Aryl-5-(2-dialkylamino-vinyl)-1H-tetrazole aus 3-Chlor-propen-iminiumsalzen

Tetrazole Compounds. 1. 1-Aryl-5-(2-dialkylamino-vinyl)-1H-tetrazoles from 3-Chloropropeniminium Salts 3-Chloropropeniminium salts 1 react with excess sodium azide in refluxing alcohols to give mainly 1-aryl-5-(2-dialkylamino-vinyl)-1H-tetrazoles 3 ; in minor quantities isomeric 5-aryl-1-(2-dialkylamino-vinyl)-1H-tetrazoles 4 are formed. The reaction involves splitting off N₂ and C → N migration of the aryl and dialkylaminovinyl group, respectively. A cross-over experiment indicated that the rearrangement step proceeds intramolecularly. — The i.r., u.v., and n.m.r. spectroscopic data of the novel 1H-tetrazoles 3 as well as the u.v. spectra of some new starting products 1k—v are reported.     

Pyryliumverbindungen. XVIII, 2-Alkoxy-2H-pyrane aus tetra- und pentasubstituierten Pyryliumsalzen

Pyrylium Compounds. XVIII. 2-Alkoxy-2H-pyrans from Tetra- and Pentasubstituted Pyrylium Salts Alkali alkoxides add regioselectively to 2,3,4,6-tetrasubstituted pyrylium salts 7 (R' H), affording high yields of colourless crystalline 2-alkoxy-2H-pyrans 9 . The latte are also formed simply on refluxing 7 in the corresponding alcohol with triethylamine as proton acceptor. 3,5-Dialkylsubstituted 2,4,6-triarylpyrylium salts react analogously. The 2H-pyran structure of the adducts obtained follows from their n.m.r., i.r., u.v. and mass spectra as well as from their reaction with tetracyanoethylene to cycloadducts of type 10 . Acids regenerate from 9 the original pyrylium cations, whereas reaction of 9 with nitromethane or ethyl cyanoacetate provides benzene derivatives. -- The novel starting pyrylium salts 7b--o are characterized by u.v./vis data and by transformation into the corresponding pyridine derivatives     

Pyryliumverbindungen. 37. Arylbenzene aus 2,4,6-Triaryl-pyryliumsalzen und Carbonsäureanhydriden

Pyrylium Compounds. 37. Arylbenzenes from 2,4,6-Triarylpyrylium Salts and Carboxylic Acid Anhydrides Refluxing 2,4,6-triarylpyrylium salts 1 with excess carboxylic acid anhydrides (RCH₂CO)₂O ( 2a : R = H, 2b : R = Me) in the presence of condensing agents like sodium or potassium acetate, sodium carbonate or methoxide, triethylamine or pyridine results in 1,3,5-triarylbenzenes 3 (R = H, Me). Under similar conditions, phenylacetic acid anhydride ( 2c ), generated in situ from sodium phenylacetate and excess 2a or 2b , yields 1,2,3,5-tetraarylbenzenes 3 (R = Ph). Thus, the reaction 1 + 2 → 3 represents a new and simple method for replacing the pyrylium heteroatom =O^⊕– by the =CR– moiety (R = H, Me, Ph). The structure of the arylbenzenes 3 was proved by spectroscopic methods, by comparison with literature data or by independent synthesis. As by-products 2-acyloxy-benzophenones 10 are formed. Reaction of 3,5-dimethyl-2,4,6-triphenyl-pyrylium perchlorate ( 11 ) with acetic acid anhydride/sodium acetate (or sodium phenylacetate) takes another course leading to 2-acetoxy-3,5-dimethyl-4,6-diphenyl-benzophenone ( 15 ), whereas treatment of 11 with propionic acid anhydride/sodium acetate follows the reaction scheme 1 + 2 → 3 giving 1,3,5-trimethyl-2,4,6-triphenylbenzene ( 16 ). The mechanisms of the different pyrylium ring transformations are discussed.