- Synthesis of N6-[endo-2′-(endo-5′-hydroxy)norbornyl] -8-(N-methylisopropylamino)-9-methyladenine (WRC-0571): A potent and selective adenosine A1 receptor antagonist
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A new versatile synthesis of N6-[endo-2′-(endo-5′- hydroxy)norbornyl]-8-(N-methylisopropylamino)-9-methyladenine (WRC-0571), a highly potent and selective antagonist for adenosine A1 receptor, is presented. The overall yield is 14%.
- Jin, Chunyang,Burgess, Jason P.,Rehder, Kenneth S.,Brine, George A.
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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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- 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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- 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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- Synthesis of novel selenotetrazole purine derivatives and their potential chemotherapeutic activities
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The development of novel chemotherapeutic agents is indispensable to improve cancer treatment. One of the conventional approaches toward the synthesis of anticancer agents is the design of a compound whose structure is similar to purines found in DNA. In this study, a series of novel artificial purine nucleosides bearing selenotetrazole pharmacophore, 4a–4h, were synthesized. In order to get preliminary information about their cytotoxic activities, the interaction of compounds with DNA was investigated by UV titration and agarose gel electrophoresis and transcription inhibition studies were performed. The cytotoxic effects of the compounds against B16 melanoma, OV90 ovarian cancer, JM1 lymphoma cell lines, and PHA-induced peripheral blood lymphocytes were also investigated. In cell assay studies, the effects of the compounds on synthesis and mitosis stage of cell cycle were compared by flow cytometry. Although none of the compounds synthesized interacted with DNA and exhibited transcription inhibition, all of them significantly inhibited DNA synthesis phase and showed cytotoxic activity on cancer and proliferating cells. [Figure not available: see fulltext.]
- Dilek, Gulay,Tekin, Ishak Ozel,Coban, Burak,Disli, Ali,Gercek, Zuhal
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- Projected Dose Optimization of Amino- And Hydroxypyrrolidine Purine PI3KδImmunomodulators
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The approvals of idelalisib and duvelisib have validated PI3Kδinhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors wit
- Methot, Joey L.,Zhou, Hua,McGowan, Meredeth A.,Anthony, Neville John,Christopher, Matthew,Garcia, Yudith,Achab, Abdelghani,Lipford, Kathryn,Trotter, Benjamin Wesley,Altman, Michael D.,Fradera, Xavier,Lesburg, Charles A.,Li, Chaomin,Alves, Stephen,Chappell, Craig P.,Jain, Renu,Mangado, Ruban,Pinheiro, Elaine,Williams, Sybill M. G.,Goldenblatt, Peter,Hill, Armetta,Shaffer, Lynsey,Chen, Dapeng,Tong, Vincent,McLeod, Robbie L.,Lee, Hyun-Hee,Yu, Hongshi,Shah, Sanjiv,Katz, Jason D.
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p. 5137 - 5156
(2021/05/04)
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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 0501
(2019/03/17)
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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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- Purine-ring-containing benzene sulfonamide chalcone derivative and preparation and application methods thereof
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The invention discloses a purine-ring-containing benzene sulfonamide chalcone derivative and preparation and application methods thereof. The purine-ring-containing benzene sulfonamide chalcone derivative has a formula (I) shown as below, in which R1 is 4-oxymethyl, 4-tert-butyl, 4-methyl, 4-flouride, 4-bromide, 2-methyl, 2-fluoride, 2-chloride, 2-bromide and hydrogen atom and R2 is methyl, ethyland benzyl. The purine-ring-containing benzene sulfonamide chalcone derivative can inhibit tobacco mosaic virus, cucumber mosaic virus, potato Y virus and southern rice black-streaked dwarf virus.
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Paragraph 0024; 0026
(2019/01/05)
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- Antiviral properties and interaction of novel chalcone derivatives containing a purine and benzenesulfonamide moiety
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A new concise and facile method was explored to synthesize a series of novel chalcone derivatives containing a purine and benzenesulfonamide moiety and their antiviral properties were evaluated against TMV and CMV. Biological assays indicated that several
- Zhou, Dagui,Xie, Dandan,He, Fangcheng,Song, Baoan,Hu, Deyu
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p. 2091 - 2097
(2018/05/08)
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- Benzylic Fluorination of Aza-Heterocycles Induced by Single-Electron Transfer to Selectfluor
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A selective and mild method for the benzylic fluorination of aromatic azaheterocycles with Selectfluor is described. These reactions take place by a previously unreported mechanism, in which electron transfer from the heterocyclic substrate to the electrophilic fluorinating agent Selectfluor eventually yields a benzylic radical, thus leading to the desired C?F bond formation. This mechanism enables high intra- and intermolecular selectivity for aza-heterocycles over other benzylic components with similar C?H bond-dissociation energies.
- Danahy, Kelley E.,Cooper, Julian C.,Van Humbeck, Jeffrey F.
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supporting information
p. 5134 - 5138
(2018/03/26)
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- Heterocyclic compound used as MNK inhibitor
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The invention relates to a heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound, a preparation method thereof, and application thereof used as a mitogen activated protein kinase interacting kinase 1 and 2-MNK1/MNK2 inhibitor. The inhibitor is the heterocyclic compound as shown in the formula (I), or its pharmaceutically acceptable salt, prodrug, solvent compound, polycrystal, isomer, stable isotope derivative or a pharmaceutical composition containing the heterocyclic compound. The compound of the invention can be used for treating or preventing MNK-mediatedrelated diseases, such as cancers.
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Paragraph 0248
(2019/01/08)
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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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- Discovery of 9H-purins as potential tubulin polymerization inhibitors: Synthesis, biological evaluation and structure?activity relationships
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Two series of N-(4-methoxyphenyl)-N-methyl-9H-purin-6-amines (9a-d and 10a-h) and 9-substituted benzyl-6-chloro-9H-purines (11a-h) were designed and synthesized. Their antiproliferative activities against human myelogenous leukemia (K562), human neuroblas
- Zhou, Zhong-Zhen,Shi, Xiu-Dong,Feng, Hong-Fang,Cheng, Yu-Fang,Wang, Hai-Tao,Xu, Jiang-Ping
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p. 1126 - 1134
(2017/08/02)
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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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- Design, synthesis and biological evaluation of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors
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By combining the scaffolds of UI-125 and Sorafenib, a series of bis-aryl ureas and amides based on 2-amino-3-purinylpyridine moiety were designed and synthesized as novel DFG-out B-RafV600E inhibitors. Among them, 20c-e, 20g and 21h displayed potent antiproliferative activities against melanoma A375 (B-RafV600E) cell lines with IC50 values of 3.190, 2.276, 1.856, 1.632 μM and 1.839 μM, respectively, comparable with the positive control Vemurafenib (IC50 Combining double low line 3.32 μM). Selected compounds were tested for the ERK inhibition in human melanoma A375 (B-RafV600E) and SK-MEL-2 (B-RafWT) cell lines by Western blot. The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-RafV600E) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-RafWT). Eventually, 20g and 21h were selected to confirm their inhibitory effects on tumor growth in A375 xenograft models in mice. Compound 20g exhibited equivalent antitumor efficacy in vivo (T/C Combining double low line 44.37%), compared to Sorafenib (T/C Combining double low line 37.35%), by 23-day repetitive administration of a single dose of 50 mg/kg without significant body weight loss.
- Yang, Weimin,Chen, Yadong,Zhou, Xiang,Gu, Yazhou,Qian, Wenqi,Zhang, Fan,Han, Wei,Lu, Tao,Tang, Weifang
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supporting information
p. 581 - 596
(2014/12/12)
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- PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
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The instant invention provides compounds of formula I which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflamation, asthma, COPD and cancer.
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Page/Page column 123
(2014/06/11)
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- Synthesis of some novel amino and thiotetrazole purine derivatives and investigation of their antimicrobial activity and DNA interactions
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A series of amino and thiotetrazole purine derivatives introduced with different alkyl groups in position 9 was synthesized. The structures of the synthesized compounds were characterized using spectroscopic methods. All the synthesized compounds were screened for their antibacterial activities against Gram-positive and Gram-negative bacteria and for their antifungal activities against yeast strains. The effect of the compounds on pBR322 plasmid DNA was studied by gel electrophoretic mobility measurements. The results of antimicrobial activity show that attachment of tetrazole group to purine bases results in disappearance of antimicrobial activity The results of the plasmid DNA interaction and the restriction studies suggest that while aminotetrazole purine derivatives cause DNA damages, thiotetrazole purine derivatives are believed to form a range of interstrand GG adducts with duplex DNA that induce global changes in the DNA conformation.
- Dilek Celik, Gulay,Disli, Ali,Oner, Yagmur,Acik, Leyla
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p. 1470 - 1479
(2013/03/29)
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- INHIBITORS OF PI3K-DELTA AND METHODS OF THEIR USE AND MANUFACTURE
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The invention is directed to Compounds of Formula I: and pharmaceutically acceptable salts or solvates thereof, as well as methods of making and using the compounds.
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Page/Page column 157-158
(2012/04/04)
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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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- PYRIMIDINE DERIVATIVES AND METHODS OF TREATMENT RELATED TO THE USE THEREOF
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The present invention encompasses novel substituted pyrimidine compounds of Formula (I): which act as MCH receptor antagonists. These compounds are useful in pharmaceutical compositions whose use includes prophylaxis or treatment of improving memory function, sleeping and arousal, anxiety, depression, mood disorders, seizure, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, binge eating disorders including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson’s disease, epilepsy, and addiction.
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Page/Page column 179
(2008/06/13)
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- Synthesis and biological evaluation of disubstituted N6- cyclopentyladenine analogues: The search for a neutral antagonist with high affinity for the adenosine A1 receptor
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Novel 3,8- and 8,9-disubstituted N6-cyclopentyladenine derivatives were synthesised in moderate overall yield from 6-chloropurine. The derivatives were made in an attempt to find a new neutral antagonist with high affinity for adenosine A1 receptors. N6-Cyclopentyl-9- methyladenine (N-0840) was used as a lead compound. Binding affinities of the new analogues were determined for human adenosine A1 and A 3 receptors. Their intrinsic activity was assessed in [ 35S]GTPγS binding experiments. Elongation of the 9-methyl of N-0840 to a 9-propyl substituent was very well tolerated. A 9-benzyl group, on the other hand, caused a decrease in adenosine A1 receptor affinity. Next, the 8-position was examined in detail, and affinity was increased with appropriate substitution. Most derivatives were A1-selective and 20 of the new compounds (6-9, 15-21, 23-26, 28, 31, 33, 35, and 36) had higher adenosine A1 receptor affinity than the reference substance, N-0840. Compound 31 (N6-cyclopentyl-8-(N-methylisopropylamino)-9- methyladenine, LUF 5608) had the highest adenosine A1 receptor affinity, 7.7 nM. In the [35S]GTPγS binding experiments, derivatives 5, 14, 22, 23, 25, 26, 33 and 34 did not significantly change basal [35S]GTPγS binding, thus behaving as neutral antagonists. Moreover, four of these compounds (23, 25, 26, and 33) displayed a 4- to 10-fold increased adenosine A1 receptor affinity (75-206 nM) compared to N-0840 (852 nM). In summary, we synthesised a range of N-0840 analogues with higher affinity for adenosine A1 receptors. In addition, four new derivatives, LUF 5666 (23), LUF 5668 (25), LUF 5669 (26) and LUF 5674 (33), behaved as neutral antagonists when tested in [ 35S]GTPγS binding studies. Thus, these compounds have improved characteristics as neutral adenosine A1 receptor antagonists.
- De Ligt, Rianne A. F.,Van Der Klein, Pieter A. M.,Von Frijtag Drabbe Kuenzel, Jacobien K.,Lorenzen, Anna,El Maate, Fatna Ait,Fujikawa, Shelly,Van Westhoven, Rosemarijn,Van Den Hoven, Thijs,Brussee, Johannes,Ijzerman, Ad P.
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p. 139 - 149
(2007/10/03)
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- Synthesis and biological activity of novel substituted pyridines and purines containing 2,4-thiazolidinedione
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A series of substituted pyridines and purines containing 2,4-thiazolidinedione were designed and synthesized from their corresponding pyridines and purines. These synthesized compounds (entry no. 6a-d, 12a-e, 18a-d, 23a-c) were evaluated for their effect on triglyceride accumulation in 3T3-L1 cells in vitro and their hypoglycemic and hypolipidemic activity in the genetically diabetic KKAy mice in vivo. On the basis of their biological activities, 5-(4-{2-[N-methyl-(5-phenyl-pyridin-2-yl)amino]ethoxy} benzyl)thiazolidine-2,4-dione (6d) was selected as a candidate for further pharmacological studies.
- Kim, Bok Young,Ahn, Joong Bok,Lee, Hong Woo,Kang, Sung Kwon,Lee, Jung Hwa,Shin, Jae Soo,Ahn, Soon Kil,Hong, Chung Il,Yoon, Seung Soo
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p. 433 - 447
(2007/10/03)
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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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- Piperazinyl derivatives of purines and isosteres thereof as hypoglycemic agents
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There are disclosed certain 6-piperazinopurines and heteroaromatic derivatives thereof which have oral hypoglycemic acitivity and with such ability to lower blood sugar are useful in the treatment of type II diabetes and/or obesity with associated insulin
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- Pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine
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New pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines have the general formula STR1 They are useful as antiinflammatory agents.
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