- Adenosine diphosphate ribose compound, preparation method and biological activity thereof
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The invention discloses an adenosine diphosphate ribose compound, which has a general formula shown as (I), wherein the definitions of all substituents are detailed in the specification. In addition,the invention also discloses a preparation method and application of the compound. The adenosine diphosphate ribose (ADPR) structural analogue provided by the invention has specific TRPM2 (transient receptor potential melastatin 2) inhibitory activity.
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- Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
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Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5′-diphosphoribose analogues were synthesized, and their activities and selectivity were evaluated. Whole-cell patch-clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a, were identified as TRPM2 inhibitors with IC50 of 5.7 and 5.4?μm, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure–activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds.
- Luo, Xiao,Li, Meng,Zhan, Kaiyu,Yang, Wei,Zhang, Lihe,Wang, KeWei,Yu, Peilin,Zhang, Liangren
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p. 552 - 566
(2017/11/21)
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- Improved Synthesis of MDL 73811 - A Potent AdoMetDC Inhibitor and Anti-Trypanosomal Compound
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An improved synthesis of MDL 73811 - a potent AdoMetDC (S-adenosylmethionine decarboxylase) inhibitor and anti-trypanosomal compound with in vivo activity - has been completed in four steps from commercially available 2′,3′-O-isopropylideneadenosine. Util
- Brockway, Anthony J.,Cosner, Casey C.,Volkov, Oleg A.,Phillips, Margaret A.,De Brabander, Jef K.
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p. 2065 - 2068
(2016/07/06)
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- α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors
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ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N6-Monosubstitution was superior to symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki 7.23 nM), N6-phenylethyl- (10h, PSB-12425, Ki 8.04 nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, Ki 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.
- Bhattarai, Sanjay,Freundlieb, Marianne,Pippel, Jan,Meyer, Anne,Abdelrahman, Aliaa,Fiene, Amelie,Lee, Sang-Yong,Zimmermann, Herbert,Yegutkin, Gennady G.,Str?ter, Norbert,El-Tayeb, Ali,Müller, Christa E.
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p. 6248 - 6263
(2015/08/24)
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- IMMUNOASSAY OF S-ADENOSYLMETHIONINE USING ANALOGS THEREOF AND PERSONALIZED THERAPEUTICS
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A method of detecting the presence or absence of a disease in a patient wherein said disease is accompanied by deficient levels of S-adenosylmethionine comprising: identifying a patient that is suspected of having said disease or is at risk of having said
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Page/Page column 39; 40
(2014/09/29)
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- Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties
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6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8- dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their Kd and IC 50 values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8- dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.
- Shi, Genbin,Shaw, Gary,Liang, Yu-He,Subburaman, Priadarsini,Li, Yue,Wu, Yan,Yan, Honggao,Ji, Xinhua
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scheme or table
p. 47 - 57
(2012/02/05)
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- NOVEL ANTIBACTERIAL COMPOUNDS
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The present invention relates to compounds of formula (I): wherein Rj, R2, R3, R4, Xi, X2, X3 and Z are as defined in claim 1. The compounds are useful in the prevention and/or treatment of bacterial infections.
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Page/Page column 22
(2012/07/14)
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- LINKED PURINE PTERIN HPPK INHIBITORS USEFUL AS ANTIBACTERIAL AGENTS
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The disclosure provides linked purine pterin compounds and analogues thereof that are novel HPPK inhibitors. The HPPK inhibitors described herein are compounds and the pharmaceutically acceptable salts thereof of general Formula I: (I). The variables, e.g. A1 to A3, R1 to R4, L1, L2, B1, and B2 are described herein. Compounds and salts of Formula I bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing an HPPK inhibitor of Formula I and methods of treating a bacterial infection in a patient by providing one or more HPPK inhibitors of Formula I to the patient are also provided. Processes and intermediates useful for preparing compounds of Formula I are also provided. Methods of using the disclosed compounds to guide the development of additional novel anti-bacterial agents are also provided.
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Page/Page column 27
(2012/01/06)
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- Antibody to 5' -Deoxy-5' - Methylthioadenosine And Uses Thereof
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The present invention provides a new immunogen, a novel antibody having high specificity for MTA (5′-deoxy-5′-methylthioadenosine), methods of treatment and medicaments prepared using said antibody, and sensitive assays for measuring spermidine synthase activity.
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Page/Page column 14
(2010/11/29)
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- Novel chemical agents comprising an adenosine moiety or an adenosine analog moiety and an imaging moiety and methods of their use
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The present invention is directed to novel chemical agents for compounds and their use for imaging myocardial perfusion. The invention also is directed to a kit for forming such novel agents. The chemical agents for the present invention comprising (a) an adenosine analog moiety or an adenosine moiety, and (b) an imaging moiety.
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Page/Page column 8; 9
(2010/02/11)
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- Synthesis of Two Stable Nitrogen Analogues of S-Adenosyl-L-methionine
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Homochiral syntheses of two stable nitrogen analogues of S-adenosyl-L-methionine (AdoMet) are described. In the first analogue, AzaAdoMet, the sulfonium center of AdoMet, is replaced by an N-methyl moiety whose pKa is 7.08. This provides a char
- Thompson, Mark J.,Mekhalfia, Abdelaziz,Hornby, David P.,Blackburn, G. Michael
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p. 7467 - 7473
(2007/10/03)
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- Nucleotides. Part XLV. Synthesis of new (2'-5')adenylate trimers, containing 5'-amino-5'-deoxyadenosine residues at the 5'-end of the oligoadenylate chain, and of its analogues, carrying a 9-[(2-hydroxyethoxy)methyl]adenine residue at the 2'-terminus
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The 5'-amino-5'-deoxy-2',3'-O-isopropylideneadenosine (4) was obtained in pure form from 2',3'-O-isopropylideneadenosine (1), without isolation of intermediates 2 and 3. The 2-(4-nitrophenyl)ethoxycarbonyl group was used for protection of the NH2 functions of 4 (→ 7). The selective introduction of the palmitoyl (= hexadecanoyl) group into the 5'-N-position of 4 was achieved by its treatment with palmitoyl chloride in MeCN in the presence of Et3N (→ 5). The 3'-O-silyl derivatives 11 and 14 were isolated by column chromatography after treatment of the 2',3'-O-deprotected compounds 8 and 9, respectively, with (tert-butyl)dimethylsilyl chloride and 1H-imidazole in pyridine. The corresponding phosphoramidites 16 and 17 were synthesized from nucleosides 11 and 14, respectively, and (cyanoethoxy)bis(diisopropylamino)phosphane in CH2Cl2. The trimeric (2'-5')-linked adenylates 25 and 26 having the 5'-amino-5'-deoxyadenosine and 5'-deoxy-5'-(palmitoylamino)adenosine residue, respectively, at the 5'-end were prepared by the phosphoramidite method. Similarly, the corresponding 5'-amino derivatives 27 and 28 carrying the 9-[(2-hydroxyethoxy)methyl]adenine residue at the 2'-terminus, were obtained. The newly synthesized compounds were characterized by physical means. The synthesized trimers 25-28 were 3-, 15-, 25-, and 34-fold, respectively, more stable towards phosphodiesterase from Crotalus durissus than the trimer (2'-5')ApApA.
- Kvasyuk,Kulak,Mikhailopulo,Charubala,Pfleiderer
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p. 1777 - 1784
(2007/10/02)
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- S-Adenosylcoenzyme M and (+/-) S-methyl adenosylcoenzyme M. Preparation and role in methane biosynthesis
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5'-S-(2-Sulphoethyl)-5'-deoxy-5'-thioadenosine (S-adenosylcoenzyme M), 5, was prepared from adenosine by reacting its 2',3'-isopropylidine tosylate with the disodium salt of coenzyme M (NaSCH2CH2SO3Na) follwed by removal of the protecting group.Methylation of 5 to give methylsulphonium (+/-) S-adenosylcoenzyme M, 6, was achieved with methyl iodide in acetic acid.Neither 5 nor 6 stimulated methane production from cell free preparations of M. thermoautotrophicum, negating the possibility of a biochemical analogy between 6 and S-adenosylmethionine (SAM).
- Cullen, William R.,Dolphin, David,Hoffman, Dale,Trip, Everard
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p. 2136 - 2139
(2007/10/02)
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- Synthesis and Conformational Analysis of Some 5'-Homoadenosine Derivatives
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The syntheses of the homoadenosines 9-(5-deoxy-β-D-ribo-hexofuranosyl)adenine (2) and 9-(5,6-dideoxy-β-ribo-heptofuranosyl)adenine (3) as well as the 5'-homo-AMP analogue 9-(5,6-dideoxy-6-phosphono-β-D-ribo-hexofuranosyl)adenine (4) are described.The conf
- Hollmann, Juergen,Schlimme, Eckhard
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