- Regioselective alkylation reaction of purines under microwave irradiation
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The alkylation of purines which is generally carried out after anion formation by treatment with a base and alkyl halide is complicated and in the best cases, mixtures of N-alkylated compounds are obtained. Purine derivatives can be acquired from alkylati
- Vinuesa, Arturo,Vi?as, Miquel,Jahani, Daniel,Ginard, Jaume,Mur, Nuria,Pujol, Maria Dolors
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p. 597 - 602
(2021/12/22)
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- OXADIAZOLE TRANSIENT RECEPTOR POTENTIAL CHANNEL INHIBITORS
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The invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof wherein A, X, R1, R4 and n are as defined herein. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.
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- 6-Substituted purines as ROCK inhibitors with anti-metastatic activity
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Rho-associated serine/threonine kinases (ROCKs) are principal regulators of the actin cytoskeleton that regulate the contractility, shape, motility, and invasion of cells. We explored the relationships between structure and anti-ROCK2 activity in a group
- Voller, Ji?í,Zahajská, Lenka,Plíhalová, Lucie,Je?ábková, Jana,Burget, David,Pataki, Andreea Csilla,Kry?tof, Vladimír,Zatloukal, Marek,Brábek, Jan,R?sel, Daniel,Mik, Václav,Tká?, Martin,Pospí?il, Tomá?,Gucky, Tomá?,Dole?al, Karel,Strnad, Miroslav
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- ECTONUCLEOTIDE PYROPHOSPHATASE-PHOSPHODIESTERASE 1 (ENPP-1) INHIBITORS AND USES THEREOF
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Disclosed herein are methods and compounds of augmenting and enhancing the production of type I IFNs in vivo. In some embodiments, the compounds disclosed herein are ENPP-1 inhibitors, pharmaceutical compositions, and methods for the treatment of cancer or a viral infection.
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Paragraph 0498
(2019/03/17)
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- Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4- d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds
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Alkylation of 4-methoxy-1H-pyrazolo[3,4-d]pyrimidine (1b) with iodomethane in THF using NaHMDS as base selectively provided N2-methyl product 4-methoxy-2-methyl-2H-pyrazolo[3,4-d]pyrimidine (3b) in an 8/1 ratio over N1-methyl product (2b). Interestingly, conducting the reaction in DMSO reversed selectivity to provide a 4/1 ratio of N1/N2 methylated products. Crystal structures of product 3b with N1 and N7 coordinated to sodium indicated a potential role for the latter reinforcing the N2-selectivity. Limits of selectivity were tested with 26 heterocycles which revealed that N7 was a controlling element directing alkylations to favor N2 for pyrazolo- and N3 for imidazo- and triazolo-fused ring heterocycles when conducted in THF. Use of 1H-detected pulsed field gradient-stimulated echo (PFG-STE) NMR defined the molecular weights of ionic reactive complexes. This data and DFT charge distribution calculations suggest close ion pairs (CIPs) or tight ion pairs (TIPs) control alkylation selectivity in THF and solvent-separated ion pairs (SIPs) are the reactive species in DMSO.
- Bookser, Brett C.,Weinhouse, Michael I.,Burns, Aaron C.,Valiere, Andrew N.,Valdez, Lino J.,Stanczak, Pawel,Na, Jim,Rheingold, Arnold L.,Moore, Curtis E.,Dyck, Brian
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p. 6334 - 6353
(2018/06/01)
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- Mechanism of Action of the Cytotoxic Asmarine Alkaloids
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The asmarines are a family of cytotoxic natural products whose mechanism of action is unknown. Here, we used chemical synthesis to reverse engineer the asmarines and understand the functions of their individual components. We found that the potent asmarine analog delmarine arrested the mammalian cell cycle in the G1 phase and that both cell cycle arrest and cytotoxicity were rescued by cotreatment with ferric and ferrous salts. Cellular iron deprivation was clearly indicated by changes in iron-responsive protein markers, and cytotoxicity occurred independently of radical oxygen species (ROS) production. Chemical synthesis allowed for annotation of the distinct structural motifs required for these effects, especially the unusual diazepine, which we found enforced an iron-binding tautomer without distortion of the NCNO dihedral angle out of plane. With this information and a correlation of cytotoxicity with logP, we could replace the diazepine by lipophilic group appendage to N9, which avoided steric clash with the N6-alkyl required to access the aminopyridine. This study transformed the asmarines, scarce marine metabolites, into easily synthesized, modular chemotypes that may complement or succeed iron-selective binders in clinical trials and use.
- Lambrecht, Michael J.,Kelly, Jeffery W.,Shenvi, Ryan A.
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p. 1299 - 1306
(2018/05/14)
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- OXADIAZOLONES AS TRANSIENT RECEPTOR POTENTIAL CHANNEL INHIBITORS
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The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula (I) as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.
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Paragraph 0169-0172
(2018/06/12)
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- Direct, Regioselective N-Alkylation of 1,3-Azoles
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Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases to affect regioselective alkylation of various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 to 95%.
- Chen, Shuai,Graceffa, Russell F.,Boezio, Alessandro A.
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supporting information
p. 16 - 19
(2016/01/15)
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- Highly efficient and broad-scope protocol for the preparation of 7-substituted 6-halopurines via N 9-Boc-protected 7,8-dihydropurines
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9-Boc-6-chloropurine, which can be obtained in high yield, is nearly quantitatively reduced with the THFBH3 complex. The obtained 9-Boc-7,8-dihydropurine derivative is more stable compared to the corresponding 9-tritylpurine and can be smoothly
- Kotek, Vladislav,Tobrman, Toma,Dvoak, Dalimil
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experimental part
p. 610 - 618
(2012/04/04)
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- Selective synthesis of 7-substituted purines via 7,8-dihydropurines
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A simple and efficient protocol for the preparation of 7-substituted purines is described. 6- and 2,6-Dihalopurines were N9-tritylated and then transformed to 7,8-dihydropurines by DIBAL-H. Subsequent N 7-alkylation followed by N9-trityl deprotection with trifluoroacetic acid was accompanied by spontaneous reoxidation, which led to the 7-substituted purines at 55 - 88% overall isolated yields.
- Kotek, Vladislav,Chudikova, Nadezda,Tobrman, Tomas,Dvorak, Dalimil
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p. 5724 - 5727
(2011/03/19)
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- Cytokinin receptor antagonists derived from 6-benzylaminopurine
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Recently we reported 6-(2-hydroxy-3-methylbenzylamino)purine (PI-55) as the first molecule to antagonize cytokinin activity at the receptor level. Here we report the synthesis and in vitro biological testing of eleven BAP derivatives substituted in the be
- Nisler, Jaroslav,Zatloukal, Marek,Popa, Igor,Dole?al, Karel,Strnad, Miroslav,Spíchal, Luká?
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experimental part
p. 823 - 830
(2010/07/04)
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- Reactivity of 6-halopurine analogs with glutathione as a radiotracer for assessing function of multidrug resistance-associated protein 1
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6-Bromo-7-[11C]methylpurine is reported to react with glutathione via glutathione S-transferases in the brain and to be converted into a substrate for multidrug resistance-associated protein 1 (MRP1), an efflux pump. The compound with a rapid c
- Okamura, Toshimitsu,Kikuchi, Tatsuya,Fukushi, Kiyoshi,Irie, Toshiaki
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experimental part
p. 7284 - 7288
(2010/08/13)
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- A novel noninvasive method for assessing glutathione-conjugate efflux systems in the brain
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Brain efflux systems export such conjugated metabolites as glutathione (GSH) and glucuronate conjugates, generated by the detoxification process, from the brain and serve to protect the brain from harmful metabolites. The intracerebral injection of a radiolabeled conjugate is a useful technique to assess brain efflux systems; however, this technique is not applicable to humans. Hence, we devised a novel noninvasive approach for assessing GSH-conjugate efflux systems using positron emission tomography. Here, we investigated whether or not a designed proprobe can deliver its GSH conjugate into the brain. Radiolabeled 6-chloro-7-methylpurine (7m6CP) was designed as the proprobe, and [14C]7m6CP was prepared by the reaction of 6-chloropurine with [14C]CH3I as a model of [11C]CH3I. The radiochemical yield and purity of [14C]7m6CP were 10-20% and greater than 99%, respectively. High brain uptake (0.8% ID/g) at 1 min was observed, followed by gradual radioactivity clearance from the brain for 5-60 min after the injection of [14C]7m6CP into rats. Analysis of metabolites confirmed that the presence of [14C]7m6CP was hardly observed, and 80% of the radioactivity was identical to its GSH conjugate for 15-60 min. The brain radioactivity was single-exponentially decreased during the period of 15-60 min post-injection of [14C]7m6CP, and the first-order efflux rate constant of the conjugate, estimated from the slope, was 0.0253 min-1. These results showed that (1) [14C]7m6CP readily entered the brain, (2) it efficiently and specifically transformed to the GSH conjugate within the brain, and (3) after [14C]7m6CP disappearance, the clearance of radioactivity represented the only efflux of GSH conjugate. We conclude that 7m6CP can deliver the GSH conjugate into the brain and would be useful for assessing GSH-conjugate efflux systems noninvasively.
- Okamura, Toshimitsu,Kikuchi, Tatsuya,Fukushi, Kiyoshi,Arano, Yasushi,Irie, Toshiaki
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p. 3127 - 3133
(2008/02/04)
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- 6-Guanidinopurine nucleosides and their analogues
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A general synthetic approach to 6-guanidinopurines, their ribonucleosides, 2-deoxyribonucleosides, acyclic nucleoside analogues and acyclic nucleoside phosphonates was developed. The approach consists in the reaction of the 6-chloropurine derivatives with guanidine solution in DMF under DABCO catalysis. This method was used to synthesize 6-guanidinopurine and 2-amino-6-guanidinopurine derivatives. Acyclic nucleosides and acyclic nucleoside phosphonates were also obtained by alkylation of the 6-guanidinopurine bases.
- Cěsnek, Michal,Holy, Antonín,Masojídková, Milena
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p. 2985 - 2996
(2007/10/03)
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