Chalkon-5′- und Flavanon-6-carbonsäuren

Chalcone-5′- and Flavanone-6-carboxylic Acids While 3-acetyl-4-hydroxybenzoic acid ( 1 ) reacts with the aldehydes 2a-c by Claisen-Schmidt reaction to the chalcone carboxylic acids 3a-c , the parent reaction with 2d is not successful. The chalcones 3a-b but not 3c can be transformed to the isomeric flavanone carboxylic acids 4a-b by common methods. 3c in MeOH/H₂SO₄ forms the methyl flavanone-carboxylate 4c which does not lead to the carboxylic acid of 4c by acid hydrolysis. Instead, 4c is split to chalcone carboxylic acid 3c quantitatively. 4′-nitroflavanone-6-carboxylic acid ( 4d ) can only be obtained by condensation of the diketones 5a-b with 4-nitrobenzaldehyd ( 2d ) as the methyl carboxylate, too. Here, instead of the expected α-aroylchalcone 6 or its tautomeric 3-aroylflavanone derivative, 4d is formed by hydrolytic removal of the arylcarboxylic acids 7a-b . The alkaline hydrolysis of compound 4d does not quantitatively afford the chalconecarboxylic acid 3d but results in destruction to a complex mixture of several compounds.     

Propyl- und Isopropylderivate der 2, 2′-Hydrazopyrimidine Mitt. Kondensationen mit Hydrazin-N,N′-dicarbonsäure-diamidin

Propyl and Isopropyl Derivatives of 2,2′-Hydrazopyrimidines Condensation of hydrazine N,N′-dicarboxylic acid diamidine (I) with β-diketones (II) in aqueous alcoholic sodium hydroxide as reaction medium at room temperature leads to 2,2′-hydrazopyrimidines (III). The new substances have been characterized by the N,N′-diacetyl derivatives and the IR′ and NMR spectra.     

Potentiell antianaphylaktische 2′- und 6-Carboxy-flavonolderivate

Potentially Antianaphylactic 2′- and 6-Carboxyflavonol Derivatives For an investigation of structure activity relationships potentially antianaphylactic (PCA assay) 2′- and 6-carboxyflavonol derivatives with a planar B-ring [2-substituted 6,13-dehydropeltogynane- 11,14-diones] and without planar structure [6-substituted 2′-carboxyflavonols] were synthesized.     

2′,5′-Dihydroxychalcone as a Potent Chemical Mediator and Cyclooxygenase Inhibitor

Eleven chalcone derivatives have been tested for their inhibitory effects on platelet aggregation in rabbit platelet suspension and the activation of mast cells and neutrophils. Arachidonic acid-induced platelet aggregation was potently inhibited by almost all the compounds and some also had a potent inhibitory effect on collagen-induced platelet aggregation and cyclooxygenase. Some hydroxychalcone derivatives showed strong inhibitory effects on the release of β-glucuronidase and lysozyme, and on superoxide formation by rat neutrophils stimulated with the peptide fMet-Leu-Phe (fMLP). We found that the anti-inflammatory effect of 2′,5′-dihydroxychalcone was greater than that of trifluoperazine. 2′,5′-Dihydroxy and 2′,3,4,4′-tetrahydroxyl chalcones, even at low concentration (50 μm), tested in platelet-rich plasma from man almost completely inhibited secondary aggregation induced by adrenaline. These results suggest that the anti-platelet effects of the chalcones are mainly a result of inhibition of thromboxane formation.     

Pharmacokinetics and Tissue Distribution of (±)-3′-Azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine,a Prodrug of 3′-Azido-2′,3′-dideoxythymidine (AZT) in Mice

The in-vivo biodistribution and pharmacokinetics in mice of 3′-azido-2′,3′-dideoxythymidine ( 1 , AZT), 2-bromomyristic acid ( 2 ) and their common prodrug, (±)-3′-azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine ( 3 ) are reported. The objectives of the work were to enhance the anti-human immunodeficiency virus and anti-fungal effects of 1 and 2 by improving their delivery to the brain and liver. The pharmacokinetics of AZT (βt1/2 (elimination, or beta-phase, half-life) = 112.5 min; AUC (area under the plot of concentration against time) = 29.1 ± 2.9 μmol g^?1 min; CL (blood clearance) = 10.5 ± 1.1 mL min^?1 kg^?1) and its ester prodrug ( 3 , βt1/2 = 428.5 min; AUC = 17.3 ± 4.7 μmol g^?1 min; CL = 17.6 ± 4.8 mL min^?1 kg^?1) were compared after intravenous injection of equimolar doses (0.3 mmol kg^?1) via the tail vein of Balb/c mice (25.30 g). The prodrug was rapidly converted to AZT in-vivo, but plasma levels of AZT (peak concentration 0.17 μmol g^?1) and AUC (12.3 μmol min g^?1) were lower than observed after AZT administration (peak concentration 0.36 μmol g^?1; AUC 29.1 μmol min g^?1). The prodrug also accumulated rapidly in the liver immediately after injection, resulting in higher concentrations of AZT than observed after administration of AZT itself (respective peak concentrations 1.11 and 0.81 μmol g^?1; respective AUCs 42.5 and 12.7 μmol min g^?1). Compared with doses of AZT itself, 3 also led to significantly higher brain concentration of AZT (25.7 compared with 9.8 nmol g^?1) and AUCs (2.8 compared with 1.4 μmol min g^?1). At the doses used in this study the antifungal agent 2-bromomyristic acid was measurable in plasma and brain within only 2 min of injection. Hepatic concentrations of 2-bromomyristic acid were higher for at least 2 h after dosing with 3 than after dosing with the acid itself. In summary, comparative biodistribution studies of AZT and its prodrug showed that the prodrug led to higher concentrations of AZT in the brain and liver. Although the prodrug did not result in measurably different concentrations of 2-bromomyristic acid in the blood and brain, it did lead to levels in the liver which were higher than those achieved by dosing with the acid itself.     

Macrocyclic peptides II. Synthesis and structure of a novel dipeptide, (2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid,and its use as the unit of cyclic peptides

A new cyclic compound [(2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid] obtained using (2S,7S)-2,7-dimethyl-3,6-diazaoctanedioic acid as a starting material was derived from N-t-butyloxycarbonyl-(2S,3′S)-2-(2′-oxo-3′-methylpiperazin-1′-yl)-propanoic acid in order to determine the molecular structure by X-ray crystal analysis. Two new macrocyclic peptides were prepared using the above cyclic compound and sarcosine as peptide units.     

Synthesis of [1,3, NH2‐15N3] (5′S)‐8,5′‐cyclo‐2′‐deoxyguanosine

To facilitate NMR studies and low‐level detection in biological samples by mass spectrometry, [1,3, NH₂‐¹⁵N₃] (5′S)‐8,5′‐cyclo‐2′‐deoxyguanosine was synthesized from imidazole‐4,5‐dicarboxylic acid in 21 steps. The three ¹⁵N isotopes were introduced during the chemo‐enzymatic preparation of [1,3, NH₂‐¹⁵N₃]‐2′‐deoxyguanosine using an established procedure. The ¹⁵N‐labeled 2′‐deoxyguanosine was converted to a 5′‐phenylthio derivative, which allowed the 8‐5′ covalent bond formation via photochemical homolytic cleavage of the C–SPh bond. SeO₂ oxidation of C‐5′ followed by sodium borohydride reduction and deprotection gave the desired product in good yield. The isotopic purity of the [1,3, NH₂‐¹⁵N₃] (5′S)‐8,5′‐cyclo‐2′‐deoxyguanosine was in excess of 99.94 atom% based on liquid chromatography–mass spectrometry measurements. Copyright © 2013 John Wiley & Sons, Ltd.     

A general synthesis of 2′‐deoxy‐2′‐[18F]fluoro‐1‐β‐D‐arabinofuranosyluracil and its 5‐substituted nucleosides

Several 2′‐deoxy‐2′‐[¹⁸F]fluoro‐1‐β‐D‐arabinofuranosyluracil derivatives have been synthesized. Coupling of 1‐bromo‐2‐deoxy‐2‐[¹⁸F]fluoro‐3,5‐di‐O‐benzoyl‐α‐D‐arabinofuranose 2 with protected uracil derivatives 3a–e followed by hydrolysis and high‐performance liquid chromatography purification produced the radiolabeled nucleosides 4a–e in 15–30% yield (d. c.), >99% radiochemical purity and 55.5–103.6 GBq/µmol specific activities. Copyright © 2003 John Wiley & Sons, Ltd.     

Darstellung und Reaktionen von 3,3′- und 2,3′-Bichromonen

Synthesis and Reactions of 3,3′- and 2,3′-Bichromones Syntheses of the 3,3′-bichromones 6a and 6b and of 2,3′-bichromone 12 are described. The following reactions of these compounds were investigated: formation of the chromylium salts 7a and 7b or 14 , of the pyrazoles 8a and 8b or 15 and of the chromenylidene derivatives 13a and 13b .     

Potentiell antianaphylaktische 5′- und 6-Carboxyflavonderivate

Potential Antianaphylactics:5′- and 6-Carboxyflavone Derivatives 2-Carboxyxanthone derivatives have antiallergic properties. Hence 2′-hydroxy-6-carboxyflavone with planar orientation of the 2-aryl group, its methyl ether without planar orientation of this group and the 4′-hydroxy and 4′-methoxy isomers were synthesized as potentially antianaphylactic analogs. 2′-Hydroxy-6-carboxyflavone gives 2′-hydroxy-5′-carboxyflavone by Wessely-Moser rearrangement.     

Untersuchungen an 1,3-Dicarbonylverbindungen, 10 Mitt. 2′-Alkylaminoflavone und 1-Alkyl-2-(2-hydroxyphenyl)-4(1 H)-chinolone

1,3-Dicarbonyl Compounds, X: 2′-Alkylaminoflavones and 1-Alkyl-2-(2-hydroxyphenyl)-4(1H)-quinolones The dibenzoylmethane derivatives 2 cyclisize with polyphosphoric acid (PPA) to yield the 2′-aminoflavones 5 . The isomeric 4-quinolones 6 are obtained by condensation of 2-hydroxy-acetophenone with 2-alkylaminobenzoates.     

Synthesis of 3′‐deoxy‐3′‐[18F]fluoro‐1‐β‐D‐xylofuranosyluracil ([18F]‐FMXU) for PET

The synthesis of a pyrimidine analog, 3′‐deoxy‐3′‐[¹⁸F]‐fluoro‐1‐β‐D ‐xylofuranosyluracil ([¹⁸F]‐FMXU) is reported. 5‐Methyluridine 1 was converted to its di‐methoxytrityl derivatives 2 and 3 as a mixture. After separation the 2′,5′‐di‐methoxytrityluridine 2 was converted to its 3′‐triflate 4 followed by derivatization to the respective N³‐t‐Boc product 5 . The triflate 5 was reacted with tetrabutylammonium[¹⁸F]fluoride to produce 6 , which by acid hydrolysis yielded compound 7 . The crude preparation was purified by HPLC to obtain the desired product [¹⁸F]‐FMXU. The radiochemical yields were 25–40% decay corrected (d. c.) with an average of 33% in four runs. Radiochemical purity was >99% and specific activity was >74 GBq/µmol at the end of synthesis (EOS). The synthesis time was 67–75 min from the end of bombardment (EOB). Copyright © 2005 John Wiley & Sons, Ltd.     

Effects of 2-methylthioadenosine 5′-β,γ-methylenetriphosphonate and 2-ethylthioadenosine 5′-monophosphate on human platelet activation induced by adenosine 5′-diphosphate

Adenosine 5′-diphosphate (ADP) induces human platelet aggregation, increases intracellular levels of free calcium, and inhibits stimulated adenylate cyclase. These effects of ADP are mediated by P_2T-purinoceptors that are inhibited specifically and competitively by adenosine 5′-triphosphate (ATP). Inhibition of ADP-induced aggregation and increases in calcium by 2-alkylthio analogs of ATP and of adenosine 5′-monophosphate (AMP) are also specific, but the inhibition is non-surmountable. To examine further the nature of inhibition of ADP-induced platelet activation by 2-alkylthio analogs, the effects of 2-methylthioadenosine 5′-β,γ-methylenetriphosphonate (2-MeS-AMP-PCP) and 2-ethylthioadenosine 5′-monophosphate (2-EtS-AMP) were tested on ADP-induced platelet aggregation and inhibition of adenylate cyclase. 2-MeS-AMP-PCP inhibited platelet aggregation induced by ADP but not by epinephrine, arachidonic acid, 5-hydroxytryptamine (5-HT), platelet activating factor (PAF), or 11α,9α-epoxymethano-prostaglandin H₂ (U46619). Inhibition of ADP-induced platelet aggregation by 2-MeS-AMP-PCP was non-surmountable, and it achieved only 50% inhibition of ADP (5 μM)-induced aggregation. 2-MeS-AMP-PCP achieved 100% inhibition of ADP (5 μM)-induced inhibition of prostaglandin E₁-stimulated adenylate cyclase, and Schild analysis showed the inhibition to be potent (pA₂ 7.3) and competitive (slope 1.12). 2-MeS-AMP-PCP inhibited platelet aggregation induced by adenosine 5′-O-2-thiodiphosphate (ADP-β-S), which inhibited stimulated adenylate cyclase activity, but did not inhibit aggregation induced by adenosine 5′-O-1-thiodiphosphate (ADP-α-S), which does not inhibit stimulated adenylate cyclase. 2-EtS-AMP behaved similarly to 2-MeS-AMP-PCP. These results suggest that ADP may induce aggregation by interacting with two forms of the calcium-mobilizing P_2T-purinoceptor, only one of which is coupled to inhibition of adenylate cyclase and at which 2-alkylthio analogs of ATP and AMP are specific competitive antagonists. © 1996 Wiley-Liss, Inc.     

Synthesis and 11C‐labelling of (E,E)‐1‐(3′,4′‐dihydroxystyryl)‐4‐(3′‐methoxy‐4′‐hydroxystyryl) benzene for PET imaging of amyloid deposits†

Carboxylic acid derivatives of the amyloid‐binding dye Congo red do not enter the brain well and are thus unable to serve as in vivo amyloid‐imaging agents. A neutral amyloid probe, (E,E)‐1‐(3′,4′‐dihydroxystyryl)‐4‐(3′‐methoxy‐4′‐hydroxystyryl)benzene ( 3 ), devoid of any carboxylate groups has been designed and synthesized via a 12‐step reaction sequence with a total yield of 30%. The unsymmetric compound 3 has also been labelled with C‐11 via [¹¹C]methyl iodide ([¹¹C]CH₃I) methylation of a symmetric 4,4′‐dimesyl protected precursor followed by deprotection. Preliminary evaluation indicated that compound 3 selectively stained plaques and neurofibrillary tangles in post‐mortem AD brain, and exhibited good binding affinity (K_i=38±8 nM) for Aβ(1–40) fibrils in vitro. In vivo pharmacokinetic studies indicated that [¹¹C] 3 exhibited higher brain uptake than its carboxylic acid analogs and good clearance from normal control mouse brain. [¹¹C] 3 also exhibited specific in vivo binding to pancreatic amyloid deposits in the NOR‐beta transgenic mouse model. These results justify further investigation of 3 and similar derivatives as surrogate markers for in vivo quantitation of amyloid deposits. Copyright © 2002 John Wiley & Sons, Ltd.     

Inhibition of histamine-induced gastric secretion by flavone-6-carboxylic acids

Twenty-five flavone-6-carboxylic acids were synthesized and tested as to their ability to inhibit histamine-induced gastric acid secretion in the rat. 3-Isopropoxy-4'-methoxyflavone-6-carboxylic acid (41) showed consistent oral activity while being devoid of any other noteworthy pharmacological effects. In vitro, this compound was found to be inactive as a histamine H2 antagonist, and its mode of action remains unknown.     

Transport properties of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine in the rat choroid plexus

Transport properties of 3′-azido-3′-deoxythymidine (AZT) and 2′, 3′-dideoxyinosine (DDI) were characterized in the isolated rat choroid plexus. AZT and DDI competitively inhibited the active transport of [³H]benzylpenicillin, a prototypic organic anion, with K_i values of 85·4±13·1 and 155±22 μM, respectively. Accumulation of [³H]DDI was against an electrochemical potential via a saturable process (K_m=29·7±4·9 μM, V_max=13·5±2·4 pmol min⁻¹/μL tissue) that was inhibited by metabolic inhibitors (carbonylcyanide p -trifluoromethoxyphenylhydrazone, 10 μM, and rotenone, 30 μM) and sulphydryl reagents (p -chloromercuribenzoic acid, 100 μM, and p -chloromercuribenzenesulphonic acid, 100 μM), but did not require an inwardly directed Na⁺ gradient. Accumulation of [³H]DDI was inhibited by benzylpenicillin and AZT in a dose-dependent manner, with IC₅₀ values of 91·6±28·9 and 294±84 μM, respectively. In contrast, no significant accumulation of [³H]AZT was observed. These results suggest that DDI is transported, at least in part, by the transport system for organic anions located on the rat choroid plexus, whereas AZT is recognized, but not transported by this system. © 1997 John Wiley & Sons, Ltd.     

Proscillaridin-3′-acylate

3′-Acylates of Proscillaridin 3′ -Acylates of proscillaridin are specifically prepared in good yields by esterification of proscillaridin with acid anhydrides or acid chlorides in the presence of boric acid and catalytic amounts of pyridine. A mechanism of this new reaction is discussed.     

Synthesis of all‐trans‐[10′‐3H]‐8′‐apo‐β‐carotenoic acid

The enzyme, 15,15′‐β‐carotene dioxygenase (BCDOX), facilitates the oxidation of β‐carotene to yield retinal. This is a remarkable process in which one of 11 double bonds in β‐carotene is selectively oxidized. To further probe the mechanistic aspects of BCDOX, the synthesis of all‐trans‐[10′‐³H]‐8′‐apo‐β‐carotenoic acid is reported. This compound will be used as a photoaffinity labeling reagent to probe the β‐carotene binding pocket within BCDOX. The synthesis outlines a simple and efficient route for the incorporation of tritium at the 10′ olefinic carbon of 8′‐apo‐β‐carotenoic acid. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [13C4]‐labeled 2′‐deoxymugineic acid

The phytosiderophore 2′‐deoxymugineic acid (DMA) is exuded via the root system by all grasses (including important crop plants like rice, wheat and barley) to mobilize Fe(III) from soil and improve plant Fe nutrition, crucial for high crop yields. Elucidation of the biogeochemistry of 2′‐deoxymugineic acid in the rhizosphere requires its quantification in minute amounts. To this end, ¹³C₄‐DMA was synthesized for the first time, from cheap isotopically labeled starting materials. The synthetic route utilizes l ‐allyl(¹³C₂)glycine and l ‐(2‐¹³C)azetidine (¹³C)carboxylic acid as versatile labeled building blocks. The title compound was recently used as an internal standard for analysis of soil and plant samples allowing the first accurate quantification of DMA in these matrices by means of LC‐MS/MS. It is furthermore used in tracer experiments investigating biodegradation of DMA in soil.     

1-(Δ 1′-Pyrrolin-2′-yl)-Δ 2-pyrroline

1-(Δ ¹-Pyrrolin-2′-yl)-Δ ²-pyrroline 2-Pyrrolidinone reacts with phosphorus ( V )chloride to yield the amidine 2 . The amidines thus prepared were characterized by their spectroscopic data and their chemical behavior. The participation of 2-chloro-Δ¹ -pyrroline ( 1 ) in the amidine formation is discussed.