- Functionalization Including Fluorination of Caffeine, Guanosine Tetraacetate, and Uridine Triacetate using Electrochemical Oxidation
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The title compounds have been subjected to electrochemical oxidation with Et3N-3HF as an electrolyte.Caffeine afforded 8-fluorocaffeine as a sole product in 43percent yield.Guanosine tetraacetate and uridine triacetate gave the fluorinated compounds in 7.3 and 4.8 percent yield, respectively.Similar electrochemical oxidation of caffeine with methanol, KCl or KCN yielded 8-methoxycaffeine, 8-chlorocaffeine, or 8-cyanocaffeine, respecticvely.
- Sono, Masakazu,Toyoda, Naoko,Shizuri, Yoshikazu,Tori, Motoo
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Read Online
- Functionalization including fluorination of nitrogen-containing compounds using electrochemical oxidation
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Nitrogen-containing compounds have been subjected to electrochemical oxidation with Et3N-3HF as an electrolyte. Caffeine afforded 8- fluorocaffeine as a sole product in 40.3% yield. Guanosine tetraacetate and uridine triacetate gave the fluorinated compounds in 17.5 and 4.6% yields, respectively. Similar electrochemical oxidation of caffeine with methanol, KCl, or KCN afforded 8-methoxycaffeine, 8-chlorocaffeine, or 8- cyanocaffeine, respectively.
- Sono, Masakazu,Toyoda, Naoko,Shimizu, Kahori,Noda, Eiji,Shizuri, Yoshikazu,Tori, Motoo
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Read Online
- 8 - Aryloxy alkoxy substituted xanthine derivative as well as preparation method and application thereof
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8 - Aryloxy alkoxy substituted xanthine derivatives as well as a preparation method and application thereof are disclosed. The xanthine derivative is substituted with 8 - chlorine as a starting material and is substituted by nucleophilic substitution. The synthesis method has the advantages of few reaction steps, simple and mild conditions, simple operation and high yield. The compound of the invention has the structural formula shown in the general formula I. The compound has a certain control effect on lepidoptera pests such as diamondback moth and oriental armyworm. At the same time, plant pathogenic fungi such as tomato early blight germ, capsici, rape sclerotiorum, cucumber Botrytis cinerea, apple wheel grain germs and wheat sheath blight bacteria have high inhibition activity. The method is suitable for comprehensive control of insect pests and germs on various crops.
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Paragraph 0036-0040; 0047-0050; 0057-0060; 0067-0070; ...
(2021/09/08)
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- Synthesis of palladium complexes with anionic N,NR- or neutral NH,NR-theophylline-derived NHC ligands
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Four C8-halogenated theophyllines (1–4) featuring N7-methyl or N7-allyl and C8-chloro or C8-bromo substituents have been prepared. The halogenotheophyllines react with [Pd(PPh3)4] in an oxidative addition to give complexes of type trans-[Pd(theophyllinato)X(PPh3)2] (trans-[5]–trans-[8]). The protonation of the unsubstituted theophyllinato ring-nitrogen atom to give the pNHC complexes was achieved either by performing the oxidative addition of 1 in the presence of NH4BF4 to give complex trans-[9]BF4 or by N-protonation of the coordinated theophyllinato ligand in trans-[6]–trans-[8] with HBF4·Et2O to give complexes trans-[10]BF4–trans-[12]BF4. The molecular structures of trans-[5], trans-[7], trans-[9]BF4, trans-[11]BF4 and trans-[12]BF4 were determined by X-ray diffraction showing significant differences of comparable metric parameters in the theophylline-derived five-membered diaminoheterocycles. No interaction of the N-allyl substituents with the metal center was observed.
- Hahn, F. Ekkehardt,Hervé, Alexandre,Jahnke, Mareike C.,Kampert, Florian
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- Synthetic Transformations of Sesquiterpene Lactones. 11.* Conjugates Based on Caffeine and Eudesmanolides with N-Containing Linkers
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8-(Aminoalkylamino)caffeine or 8-(piperazinyl)caffeine were formed in high yields by reacting 8-bromo- or 8-chlorocaffeine with linear and cyclic diamines using microwave-assisted organic synthesis. These amines were highly reactive in Michael reactions with sesquiterpene lactones containing active methylene groups. Conjugates with caffeine and eudesmanolide moieties bonded by a N-containing linker were synthesized.
- Reshetnikov,Patrushev,Shults
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p. 855 - 860
(2020/09/21)
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- Amplification of Trichloroisocyanuric Acid (TCCA) Reactivity for Chlorination of Arenes and Heteroarenes via Catalytic Organic Dye Activation
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Heteroarenes and arenes that contain electron-withdrawing groups are chlorinated in good to excellent yields (scalable to gram scale) using trichloroisocyanuric acid (TCCA) and catalytic Brilliant Green (BG). Visible-light activation of BG serves to amplify the electrophilic nature of TCCA, providing a mild alternative approach to acid-promoted chlorination of deactivated (hetero)aromatic substrates. The utility of the TCCA/BG system is demonstrated through comparison to other chlorinating reagents and by the chlorination of pharmaceuticals including caffeine, lidocaine, and phenazone.
- Rogers, David A.,Bensalah, Adam T.,Espinosa, Alvaro Tomas,Hoerr, John L.,Refai, Fares H.,Pitzel, Amy K.,Alvarado, Juan J.,Lamar, Angus A.
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supporting information
p. 4229 - 4233
(2019/06/17)
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- Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes
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Fosu, Hambira, and colleagues describe the direct C–H functionalization of medicinally relevant arenes or heteroarenes. This strategy is enabled by transient generation of reactive, non-symmetric iodanes from anions and PhI(OAc)2. The site-selective incorporation of Cl, Br, OMs, OTs, and OTf to complex molecules, including within medicines and natural products, can be conducted by the operationally simple procedure included herein. A computational model for predicting site selectivity is also included. The discovery of new medicines is a time- and labor-intensive process that frequently requires over a decade to complete. A major bottleneck is the synthesis of drug candidates, wherein each complex molecule must be prepared individually via a multi-step synthesis, frequently requiring a week of effort per molecule for thousands of candidates. As an alternate strategy, direct, post-synthetic functionalization of a lead candidate could enable this diversification in a single operation. In this article, we describe a new method for direct manipulation of drug-like molecules by incorporation of motifs with either known pharmaceutical value (halides) or that permit subsequent conversion (pseudo-halides) to medicinally relevant analogs. This user-friendly strategy is enabled by combining commercial iodine reagents with salts and acids. We expect this simple method for selective, post-synthetic incorporation of molecular diversity will streamline the discovery of new medicines. A strategy for C–H functionalization of arenes and heteroarenes has been developed to allow site-selective incorporation of various anions, including Cl, Br, OMs, OTs, and OTf. This approach is enabled by in situ generation of reactive, non-symmetric iodanes by combining anions and bench-stable PhI(OAc)2. The utility of this mechanism is demonstrated via para-selective chlorination of medicinally relevant arenes, as well as site-selective C–H chlorination of heteroarenes. Spectroscopic, computational, and competition experiments describe the unique nature, reactivity, and selectivity of these transient, unsymmetrical iodanes.
- Fosu, Stacy C.,Hambira, Chido M.,Chen, Andrew D.,Fuchs, James R.,Nagib, David A.
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supporting information
p. 417 - 428
(2019/02/14)
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- MLKL INHIBITORS
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Purine derivatives that inhibit cellular necroptosis and/or human MLKL, pharmaceutical compositions thereof, and methods of treating an MLKL-mediated disorder with an effective amount of the compound or composition. Said MLKL-mediated disorder is pathology associated necroptosis, including ischemia-reperfusion damage, neurodegeneration, and inflammatory diseases such as acute pancreatitis, multiple sclerosis, inflammatory bowel disease, and allergic colitis.
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Paragraph 0117-0118; 0778-0780
(2018/09/26)
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- Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein
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We report the development of novel Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitors with single nanomolar potency (compound 15 is also named as TC13172). Using the converting biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we were able to determine that the inhibitors covalently bind to Cysteine86 (Cys-86) of MLKL. This is the first example of the use of LC-MS/MS to identify the binding site of an MLKL inhibitor. The novel MLKL inhibitors provide powerful tools to study the biological function of MLKL and demonstrate that MLKL should be viewed as a druggable target.
- Yan, Bo,Liu, Lei,Huang, Shaoqiang,Ren, Yan,Wang, Huayi,Yao, Zhenglin,Li, Lin,Chen, She,Wang, Xiaodong,Zhang, Zhiyuan
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supporting information
p. 3637 - 3640
(2017/04/03)
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- Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells
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We report design and synthesis of set of novel anticancer agents based on caffeine-hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and great selectivity index toward T-lymphoblastic leukaemia cells. In general, hydrazones bearing 2-N-heteroaryl moiety are more active and selective than those with 2-hydroxyaryl moiety. Tested compounds exhibit dose-dependent inhibition of both RNA and DNA synthesis, with some exceptions. Antimicrobial activities were tested on set of twelve bacterial and yeast strains, however prepared compounds were not active, suggesting for a molecular target specific for eukaryotic cells.
- Kaplánek, Robert,Jakubek, Milan,Rak, Jakub,Kejík, Zdeněk,Havlík, Martin,Dolensky, Bohumil,Frydrych, Ivo,Hajdúch, Marián,Kolá?, Milan,Bogdanová, Kate?ina,Králová, Jarmila,D?ubák, Petr,Král, Vladimír
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- A practical lewis base catalyzed electrophilic chlorination of arenes and heterocycles
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A mild phosphine sulfide catalyzed electrophilic halogenation of arenes and heterocycles that utilizes inexpensive and readily available N-halosuccinimides is disclosed. This methodology is shown to efficiently chlorinate diverse aromatics, including simple arenes such as anthracene, and heterocycles such as indoles, pyrrolopyrimidines, and imidazoles. Arenes with Lewis acidic moieties also proved amenable, underscoring the mild nature of this chemistry. Lewis base catalysis was also found to improve several diverse aromatic brominations and iodinations.
- Maddox, Sean M.,Nalbandian, Christopher J.,Smith, Davis E.,Gustafson, Jeffrey L.
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supporting information
p. 1042 - 1045
(2015/03/30)
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- The inhibition of monoamine oxidase by 8-(2-phenoxyethoxy)caffeine analogues
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Previous studies have documented that substituted 8-oxycaffeines act as inhibitors of human monoamine oxidase (MAO) B. A particularly potent inhibitor among the reported compounds was 8-(2-phenoxyethoxy)caffeine with an IC 50 value of 0.383M towards MAO-B. In an attempt to improve on the inhibition potency of this compound and to discover highly potent reversible MAO-B inhibitors, in the present study, a series of 8-(2-phenoxyethoxy)caffeine analogues containing various substituents on C4 of the phenoxy ring, were synthesized and evaluated as inhibitors of human MAO-A and -B. The results show that the 8-(2-phenoxyethoxy)caffeine analogues are selective and reversible MAO-B inhibitors with the most potent homologue, 8-{2-[4-(trifluoromethyl) phenoxy]ethoxy}caffeine, exhibiting an IC50 value of 0.061μM. These highly potent inhibitors are useful leads in the design of therapies for neurodegenerative disorders such as Parkinsons disease. Georg Thieme Verlag KG Stuttgart New York.
- Strydom,Bergh,Petzer
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p. 513 - 518
(2013/01/15)
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- Inhibition of monoamine oxidase by 8-[(phenylethyl)sulfanyl]caffeine analogues
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In a previous study we have investigated the monoamine oxidase (MAO) inhibitory properties of a series of 8-sulfanylcaffeine analogues. Among the compounds studied, 8-[(phenylethyl)sulfanyl]caffeine (IC50 = 0.223 μM) was found to be a particularly potent inhibitor of the type B MAO isoform. In an attempt to discover potent MAO inhibitors and to further examine the structure-activity relationships (SAR) of MAO inhibition by 8-sulfanylcaffeine analogues, in the present study a series of 8-[(phenylethyl)sulfanyl]caffeine analogues were synthesized and evaluated as inhibitors of human MAO-A and -B. The results document that substitution on C3 and C4 of the phenyl ring with alkyl groups and halogens yields 8-[(phenylethyl)sulfanyl]caffeine analogues which are potent and selective MAO-B inhibitors with IC50 values ranging from 0.017 to 0.125 μM. The MAO inhibitory properties of a series of 8-sulfinylcaffeine analogues were also examined. The results show that, compared to the corresponding 8-sulfanylcaffeine analogues, the 8-sulfinylcaffeins are weaker MAO-B inhibitors. Both the 8-sulfanylcaffeine and 8-sulfinylcaffeine analogues were found to be weak MAO-A inhibitors. This study also reports the MAO inhibition properties of selected 8-[(phenylpropyl)sulfanyl]caffeine analogues.
- Mostert, Samantha,Mentz, Wayne,Petzer, Anél,Bergh, Jacobus J.,Petzer, Jacobus P.
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p. 7040 - 7050
(2013/01/15)
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- 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase
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Recently it was reported that a series of 8-benzyloxycaffeine analogues are potent reversible inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to discover additional C8 oxy substituents of caffeine that lead to potent MAO inhibition, a series of related 8-aryl- and alkyloxycaffeine analogues were synthesized and their MAO-A and -B inhibition potencies were compared to those of the 8-benzyloxycaffeines. The results document that while the 8-substituted-oxycaffeine analogues inhibited both human MAO isoforms, they displayed a high degree of selectivity for MAO-B. 8-(3-Phenylpropoxy)caffeine, 8-(2-phenoxyethoxy)caffeine and 8-[(5-methylhexyl)oxy]caffeine were found to be the especially potent MAO-B inhibitors with IC50 values ranging from 0.38 to 0.62 μM. These inhibitors are therefore 2.5-4.6 fold more potent MAO-B inhibitors than is 8-benzyloxycaffeine (IC50 = 1.77 μM). It is also demonstrated that, analogous to 8-benzyloxycaffeine, halogen substitution on the phenyl ring of the C8 substituent significantly enhances MAO binding affinity. For example, the most potent MAO-B inhibitor of the present series is 8-[2-(4-bromophenoxy)ethoxy]caffeine with an IC50 value of 0.166 μM. This study also reports possible binding orientations of selected oxy caffeines within the active site cavities of MAO-A and MAO-B.
- Strydom, Belinda,Bergh, Jacobus J.,Petzer, Jacobus P.
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body text
p. 3474 - 3485
(2011/07/29)
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- Inhibition of monoamine oxidase by 8-benzyloxycaffeine analogues
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Based on recent reports that several (E)-8-styrylcaffeinyl analogues are potent reversible inhibitors of monoamine oxidase B (MAO-B), a series of 8-benzyloxycaffeinyl analogues were synthesized and evaluated as inhibitors of baboon liver MAO-B and recombinant human MAO-A and -B. The 8-benzyloxycaffeinyl analogues were found to inhibit reversibly both MAO isoforms with enzyme-inhibitor dissociation constants (Ki values) ranging from 0.14 to 1.30 μM for the inhibition of human MAO-A, and 0.023-0.59 μM for the inhibition of human MAO-B. The most potent MAO-A inhibitor was 8-(3-methylbenzyloxy)caffeine while 8-(3-bromobenzyloxy)caffeine was the most potent MAO-B inhibitor. The analogues inhibited human and baboon MAO-B with similar potencies. A quantitative structure-activity relationship (QSAR) study indicated that the MAO-B inhibition potencies of the 8-benzyloxycaffeinyl analogues are dependent on the Hansch lipophilicity (π) and Hammett electronic (σ) constants of the substituents at C-3 of the benzyloxy ring. Electron-withdrawing substituents with a high degree of lipophilicity enhance inhibition potency. These results are discussed with reference to possible binding orientations of the inhibitors within the active site cavities of MAO-A and -B.
- Strydom, Belinda,Malan, Sarel F.,Castagnoli Jr., Neal,Bergh, Jacobus J.,Petzer, Jacobus P.
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experimental part
p. 1018 - 1028
(2010/04/26)
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- A simple HPLC-UV method for the determination of dimenhydrinate and related substances - Identification of an unknown impurity
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During the revision of the dimenhydrinate monograph of the European Pharmacopoeia a HPLC-UV method was developed. The procedure described allows a qualitative and quantitative determination of both dimenhydrinate compounds and of thirteen related substances. Furthermore a hitherto unknown impurity was identified and integrated into the purity check. Also 18 samples of dimenhydrinate have been tested. Thereby the relevant impurities of dimenhydrinate could be nominated and quantified.
- Doege, Ulrica,Eger
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p. 174 - 178
(2008/02/01)
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- Synthesis of 8-substituted xanthine derivatives by Suzuki cross-coupling reaction
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A Suzuki cross-coupling reaction procedure was developed to prepare 8-substituted 3,7-dihydropurine-2,6-dione (xanthine) derivatives. 8-Halogen-substituted xanthines were reacted with phenyl- and styrylboronic acids. The best results were obtained using tetrakis(triphenylphosphine)palladium(0) and tripotassium phosphate in dimethylformamide. The developed procedure allows for a convergent synthesis of pharmacologically active 8-substituted xanthine derivatives.
- Vollmann, Karl,Mueller, Christa E.
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p. 871 - 879
(2007/10/03)
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- Synthesis and Properties of 8-Nitro-7-Alkylated Theophylline Derivatives
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8-Nitrotheophylline (3) was alkylated with alkylhalides to obtain the corresponding 8-nitro-7-alkylated theophylline derivatives (4a-d).The reduction of 4a-d provided 8-aminoderivatives (5a-d).Heating 4a-d in the concentrated HCl gave the corresponding 8-chloroderivatives (6a-d).The products 5a and 5b reacted with 4-acetamidobenzenesulphonyl chloride to provide 8-(4'-acetamidobenzenesulphonamido)theophyllines (7a) and (7b).The acid hydrolysis of 7a and 7b gave the corresponding 8-(4'-aminobenzenesulphonamido)theophyllines (8a) and (8b), which were also products of the reaction of 6b and 6c with 4-acetamidobenzenesulphonamide, followed by the acid hydrolysis.The reaction of 6a and 6b with benzylamine in dimethylformamide resulted unexpectedly in the 8-dimethylaminoderivatives (9a) and (9b), respectively. Key words: 8-nitrotheophylline, alkylhalides, HCl, acid hydrolysis.
- Mosselhi, Mosselhi A. N.,Abbass, Ikhlass M.
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p. 179 - 186
(2007/10/02)
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- SOME NEW HALO- AND CYANO-DEMERCURATION REACTIONS OF 8-ACETOXYMERCURI- AND 8,8'-MERCURIBIS-CAFFEINES
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On acting upon 8-acetoxymercuri-caffeine (1) and/or 8,8'-mercuribis-caffeine (2) with aqueous solutions of KI3, KBr3, ICN, BrCN or with an excess of neat liquid SO2Cl2, SCl2, S2Cl2, and SF4, the following 8-X-substituted caffeines, X=CN (3), I (4), Br (5), Cl (6), and F (7), were prepared, sometimes in excellent yields.Seven of these methods of demercuration of organomercurials have not been reported so far in the literature.
- Skulski, Lech,Wroczynski, Piotr
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p. 975 - 982
(2007/10/02)
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