- 2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes
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CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.
- Bhattarai, Sanjay,Pippel, Jan,Scaletti, Emma,Idris, Riham,Freundlieb, Marianne,Rolshoven, Georg,Renn, Christian,Lee, Sang-Yong,Abdelrahman, Aliaa,Zimmermann, Herbert,El-Tayeb, Ali,Müller, Christa E.,Str?ter, Norbert
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supporting information
p. 2941 - 2957
(2020/04/10)
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- Synthesis and biological evaluation of a novel C8-pyrrolobenzodiazepine (PBD) adenosine conjugate. A study on the role of the PBD ring in the biological activity of PBD-conjugates
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Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD-ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to affect and modulate the biological and biophysical properties of PBD hybrids.
- Bhakta, Sanjib,Brucoli, Federico,Ferguson, Lindsay,Fox, Keith R.,Wells, Geoff
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supporting information
(2020/03/19)
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- S-Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C-Alkylation
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A tandem enzymatic strategy to enhance the scope of C-alkylation of small molecules via the in situ formation of S-adenosyl methionine (SAM) cofactor analogues is described. A solvent-exposed channel present in the SAM-forming enzyme SalL tolerates 5′-chloro-5′-deoxyadenosine (ClDA) analogues modified at the 2-position of the adenine nucleobase. Coupling SalL-catalyzed cofactor production with C-(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO forms C-(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influence C-alkylation provides the basis to develop a late-stage enzymatic platform for the preparation of high value small molecules.
- McKean, Iain J. W.,Sadler, Joanna C.,Cuetos, Anibal,Frese, Amina,Humphreys, Luke D.,Grogan, Gideon,Hoskisson, Paul A.,Burley, Glenn A.
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supporting information
p. 17583 - 17588
(2019/11/11)
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- Synthesis, characterization and biological evaluation of purine nucleoside analogues
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We present a convenient route for the synthesis of C6-amino-C5′-N-cyclopropyl carboxamido-C2-alkynylated purine nucleoside analogues 11a–g via Sonogashira coupling reaction. The nine step synthesis is easy to perform, employing commercially available reagents. Compound 9 is used as key intermediate for the synthesis of analogues 11a–g. Synthetic intermediates and final products are appropriately characterized by IR, 1H NMR, 13C NMR and Mass. The modified nucleoside analogues 11a–g is evaluated for in vitro anticancer activity against MDA-MB-231 and Caco-2 cell lines. Screening data reveals that compounds 11b and 11e displayed potent IC50 value of 7.9, 6.8 μg/mL respectively against MDA-MB-231 and of 7.5, 8.3 μg/mL respectively against Caco-2 than the standard drug doxorubicin, thus establishing the potential anti-cancer properties of these newer derivatives.
- Malthum, Shankaraiah,Polkam, Naveen,Allaka, Tejeswara Rao,Chepuri, Kalyani,Anireddy, Jaya Shree
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supporting information
p. 4166 - 4168
(2017/10/13)
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- A New Class of Fluorinated A2A Adenosine Receptor Agonist with Application to Last-Step Enzymatic [18F]Fluorination for PET Imaging
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The A2A adenosine receptor belongs to a family of G-coupled protein receptors that have been subjected to extensive investigation over the last few decades. Due to their prominent role in the biological functions of the heart, lungs, CNS and brain, they have become a target for the treatment of illnesses ranging from cancer immunotherapy to Parkinson's disease. The imaging of such receptors by using positron emission tomography (PET) has also been of interest, potentially providing a valuable tool for analysing and diagnosing various myocardial and neurodegenerative disorders, as well as offering support to drug discovery trials. Reported herein are the design, synthesis and evaluation of two new 5′-fluorodeoxy-adenosine (FDA)-based receptor agonists (FDA-PP1 and FDA-PP2), each substituted at the C-2 position with a terminally functionalised ethynyl unit. The structures enable a synthesis of 18F-labelled analogues by direct, last-step radiosynthesis from chlorinated precursors using the fluorinase enzyme (5′-fluoro-5′-deoxyadenosine synthase), which catalyses a transhalogenation reaction. This delivers a new class of A2A adenosine receptor agonist that can be directly radiolabelled for exploration in PET studies.
- Lowe, Phillip T.,Dall'Angelo, Sergio,Mulder-Krieger, Thea,IJzerman, Adriaan P.,Zanda, Matteo,O'Hagan, David
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p. 2156 - 2164
(2017/10/07)
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- Synthesis, characterization and biological evaluation of C5′-N-cyclopropylcarboxamido-C6-amino-C2-alkynylated purine nucleoside analogues
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In an effort to develop potent antibacterial and anticancer agents, a series of C5′-N-cyclopropylcarboxamido-C6-amino-C2-alkynylated purine nucleoside analogues 11a-g were synthesized through a Sonogashira cross-coupling reaction. The nine-step synthesis is easy to perform, and employs commercially available reagents. 2-Iodo-5′-N-cyclopropylcarboxamidoadenosine (9) was used as the starting intermediate for the synthesis of title derivatives 11a-g. Synthetic intermediates (2–9) and final products (11a-g) were appropriately characterized by IR, 1H NMR, 13C NMR and mass spectroscopy. The synthesized purine nucleoside analogues (11a-g) were evaluated for their in vitro antibacterial activity against two gram-positive and two gram-negative bacteria. They were then tested for cytotoxicity against MDA-MB-231 and Caco-2 cancer cell lines to determine their anti-cancer activity. Among the tested compounds, compounds 11c and 11g showed most potent antibacterial activity against S.aureus and P.aeruginosa bacterial strains. Compounds 11b and 11e displayed considerable IC50s of 7.9 and 6.8 μg/mL, respectively, vs MDA-MB-231 cell lines of 7.5 and 8.3 μg/mL, respectively, against the Caco-2 cell lines.
- Ananda Mohan, Arasavelli,Veera Raghava Sharma, Ganapavarapu,Vidavalur, Siddaiah
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p. 637 - 651
(2017/12/06)
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- Discovery of Leucyladenylate Sulfamates as Novel Leucyl-tRNA Synthetase (LRS)-Targeted Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitors
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Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that 18 may offer a novel treatment option for human colorectal cancer.
- Yoon, Suyoung,Kim, Jong Hyun,Kim, Sung-Eun,Kim, Changhoon,Tran, Phuong-Thao,Ann, Jihyae,Koh, Yura,Jang, Jayun,Kim, Sungmin,Moon, Hee-Sun,Kim, Won Kyung,Lee, Sangkook,Lee, Jiyoun,Kim, Sunghoon,Lee, Jeewoo
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p. 10322 - 10328
(2016/12/07)
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- Synthesis and evaluation of 2-ethynyl-adenosine-5′-triphosphate as a chemical reporter for protein AMPylation
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Protein AMPylation is a posttranslational modification (PTM) defined as the transfer of an adenosine monophosphate (AMP) from adenosine triphosphate (ATP) to a hydroxyl side-chain of a protein substrate. One recently reported AMPylator enzyme, Vibrio outer protein S (VopS), plays a role in pathogenesis by AMPylation of Rho GTPases, which disrupts crucial signaling pathways, leading to eventual cell death. Given the resurgent interest in this modification, there is a critical need for chemical tools that better facilitate the study of AMPylation and the enzymes responsible for this modification. Herein we report the synthesis of 2-ethynyl-adenosine-5′-triphosphate (2eATP) and its utilization as a non-radioactive chemical reporter for protein AMPylation.
- Creech, Christa,Kanaujia, Mukul,Causey, Corey P.
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p. 8550 - 8555
(2015/08/06)
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- A localized tolerance in the substrate specificity of the fluorinase enzyme enables "last-step" 18F fluorination of a RGD peptide under ambient aqueous conditions
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A strategy for last-step 18F fluorination of bioconjugated peptides is reported that exploits an "Achilles heel" in the substrate specificity of the fluorinase enzyme. An acetylene functionality at the C-2 position of the adenosine substrate projects from the active site into the solvent. The fluorinase catalyzes a transhalogenation of 5-chlorodeoxy-2- ethynyladenosine (ClDEA) to 5-fluorodeoxy-2-ethynyladenosine (FDEA). Extending a polyethylene glycol linker from the terminus of the acetylene allows the presentation of bioconjugation cargo to the enzyme for 18F labelling. The method uses an aqueous solution (H218O) of [ 18F]fluoride generated by the cyclotron and has the capacity to isotopically label peptides of choice for positron emission tomography (PET).
- Thompson, Stephen,Zhang, Qingzhi,Onega, Mayca,McMahon, Stephen,Fleming, Ian,Ashworth, Sharon,Naismith, James H.,Passchier, Jan,O'Hagan, David
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supporting information
p. 8913 - 8918
(2014/10/15)
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- SELECTIVE ANTAGONISTS OF A2A ADENOSINE RECEPTORS
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The present invention provides compounds of formulae (Ia) and (Ib): wherein R1-5, Q, X, Y, Z, p, q, and r are as defined herein. The compounds are potent and selective antagonists of A2A adenosine receptors (ARs). The invention furth
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Page/Page column 27
(2008/06/13)
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- RNA as scaffold for pyrene excited complexes
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Synthesis and spectral properties of 1-ethynylpyrene base modified RNA are reported. The fluorophore attached to the 2-position of adenosine is directed into the easily accessible minor groove in RNA. Through an intermolecular interaction of the pyrene residues in twofold labelled RNA, single and double strands can be distinguished by their fluorescence maxima around 450 and 480 nm, respectively. This behaviour allows the kinetic investigation of RNA hybridisation and folding by fluorescence spectroscopy.
- Gruenewald, Christian,Kwon, Taewoo,Piton, Nelly,Foerster, Ute,Wachtveitl, Josef,Engels, Joachim W.
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- INDUCTION OF PHARMACOLOGICAL STRESS WITH ADENOSINE RECEPTOR AGONISTS
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A method is provided employing A2A adenosine receptor agonists as vasodilators to detect the presence and assess the severity of coronary artery stenosis.
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Page/Page column 9
(2010/02/10)
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- SELECTIVE ANTAGONISTS OF A2A ADENOSINE RECEPTORS
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Selective antagonists of A2A adenosine receptors are provided. The novel A2A blockers are useful for the treatment of Parkinson's disease and other diseases.
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Page/Page column 37
(2008/06/13)
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- N-alkoxysulfamide, N-hydroxysulfamide, and sulfamate analogues of methionyl and isoleucyl adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases
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A series of sulfamate surrogates of methionyl and isoleucyl adenylate have been investigated as MetRS and IleRS inhibitors by modifications of the sulfamate linker and adenine moieties. The discovery of 2-iodo Ile-NHSO2-AMP (58) as a potent Escherichia coli IleRS inhibitor revealed that a significant hydrophobic interaction between the 2-substituent of Ile-NHSO2-AMP and the adenine binding site of IleRS provided its high potency to the enzyme.
- Lee, Jeewoo,Kim, Sung Eun,Lee, Ji Young,Kim, Su Yeon,Kang, Sang Uk,Seo, Seung Hwan,Chun, Moon Woo,Kang, Taehee,Choi, Soo Young,Kim, Hea Ok
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p. 1087 - 1092
(2007/10/03)
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- N6-alkyl-2-alkynyl derivatives of adenosine as potent and selective agonists at the human adenosine A3 receptor and a starting point for searching A2B ligands
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A series of N6-alkyl-2-alkynyl derivatives of adenosine (Ado) have been synthesized and evaluated for their affinity at human A1, A2, and A3 receptors and for their potency at A2B adenosine receptor s
- Volpini, Rosaria,Costanzi, Stefano,Lambertucci, Catia,Taffi, Sara,Vittori, Sauro,Klotz, Karl-Norbert,Cristalli, Gloria
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p. 3271 - 3279
(2007/10/03)
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- Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: Elucidation of a novel binding mode for a 2-Amino-N6-substituted adenosine
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As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N6-, 2-amino-N6-, and N2-substituted adenosine analogues were synthesized and tested to establish structure - activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for N6-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N6-[2-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 μM. 2-[[2-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 μM. To explore the potential of an additive effect that having the N6 and N2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N6,N2-disubstituted adenosine analogues to yield N6-(2-phenylethyl)-2-[(2-phenylethyl)amino]adenosine (69) as a 30 μM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 A? X-ray structure of a T. brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this 'flipped and rotated' binding mode.
- Bressi,Choe,HoughHough,Buckner,Van Voorhis,Verlinde,Hol,Gelb
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p. 4135 - 4150
(2007/10/03)
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- Synthesis of complex ethynyladenosines using organic triflic enolates in palladium-atalyzed reactions: Potential agonists for the adenosine A2 receptor
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Many high affinity adenosine A2 receptor agonists contain substituents at position 2 of the purine base. In the search for new methodology to develop C-2 substituted adenosine analogues, we have applied organic triflates in palladium-catalyzed cross-couplings that resulted in new 2-cycloalkylated ethynyl-adenosines. The organic triflates are derived from commercially available ketones and, when used in the crosscouplings, result generally in clean reactions with good yields. These are the first examples of the utilization of organic triflates in palladium-catalyzed cross-coupling reactions in the synthesis of modified nucleosides.
- Adah, Steven A.,Nair, Vasu
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p. 6747 - 6754
(2007/10/03)
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- Nucleosides and nucleotides. 103. 2-Alkynyladenosines: A novel class of selective adenosine A2 receptor agonists with potent antihypertensive effects
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The synthesis and receptor-binding activities at A1 and A2 adenosine receptors for a series of 2-alkynyladenosines are described. The palladium- catalyzed cross-coupling reaction of 2-iodoadenosine (4a) with various terminal alkynes
- Matsuda,Shinozaki,Yamaguchi,Homma,Nomoto,Miyasaka,Watanabe,Abiru
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p. 241 - 252
(2007/10/02)
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- 2-alkynyladenosines as antihypertensive agents
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A 2-alkynyladenosine represented by general formula [I]: STR1 wherein n is an integer of from 2 to 15, has been found to have excellent properties as an antihypertensive agent. On the basis of this finding, the present invention has provided an antihypertensive agent comprising an antihypertensive effective amount of a compound of the above formula [I] and a pharmaceutically acceptable carrier. The present invention also discloses a novel compound 2-alkynyladenosine of formula [I] shown above wherein n is 6 to 15.
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- Photoinduced Alkylthiolation of Halogenated Purine Nucleosides
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A new highly efficient methodology for the synthesis of biologically important methylmercaptopurine nucleosides is described.The approach represents a substantial improvement over earlier reported methods for this class of compounds.
- Nair, Vasu,Young, David A.
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p. 450 - 453
(2007/10/02)
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