362-43-6Relevant articles and documents
5',6'-Nucleoside phosphonate analogues architecture: Synthesis and comparative evaluation towards metabolic enzymes
Gallier, Franck,Alexandre, Julie A. C.,ElAmri, Chahrazade,Deville-Bonne, Dominique,Peyrottes, Suzanne,Perigaud, Christian
, p. 1094 - 1106 (2011)
Nucleoside phosphonates have been designed as stable 5'-mononucleotide mimics and are nowadays considered a potent class of antiviral agents. Within cells, they must be metabolised to the corresponding diphosphate to exert their biological activity. In this process, the first phosphorylation step, catalysed by nucleoside monophosphate kinases (NMP kinases), has been proposed as a bottleneck. Herein, we report the synthesis of a series of ribonucleoside phosphonate derivatives isosteric to 5'-mononucleotides, with different degrees of flexibility within the 5',6'-C-C bond, as well as different polarities, through the introduction of hydroxy groups. The influence of these modifications on the capacity of the compounds to act as substrates for appropriate human NMP kinases, involved in nucleic acids metabolism, has been investigated. Low flexibility, as well as an absence of hydroxy groups within the ribose-phosphorus architecture, is critical for efficient phosphotransfer. Among the series of pyrimidine analogues, one derivative was shown to be phosphorylated by human UMP-CMP kinase, with rates similar to those of dUMP and even better than dCMP. Mimicking nature: A series of ribonucleoside phosphonate analogues were synthesized, and among them, a pyrimidine derivative was shown to be phosphorylated by hUMP-CMP kinase, with rates similar to those of dUMP and even better than dCMP. Furthermore, one purine derivative was found to be phosphorylated by hAMP kinases1 and2 with improved efficiency over tenofovir.
Flexible nucleobase receptor - Effect of self-preorganization of artificial receptor
Kuroda, Yasuhisa,Lintuluoto, Juha M.,Ogoshi, Hisanobu
, p. 3729 - 3732 (1994)
A new type flexible receptor which has two uracil moieties connected with a long alkyl chain was synthesized and its molecular recognition ability toward adenine derivatives was investigated. The present receptor shows equilibrium between two states, open and close forms. In contrast to the open form, the closed form exhibits enthalpically less favorable but entropically more favorable molecular recognition toward adenine derivatives. This observation is rationally explained by the effect of self-preorganization of the present receptor.
Rapid Synthesis of a Natural Product-Inspired Uridine Containing Library
Chen, Wei-An,Cheng, Wei-Chieh,Hu, Kung-Hsiang,Lin, Yan-Ting,Liu, Wan-Ju,Lo, Lee-Chiang,Tan, Yee-Ling
, p. 600 - 607 (2020)
The preparation of natural product-inspired nucleoside analogs using solution-phase parallel synthesis is described. The key intermediates containing alkyne and N-protected amino moieties were developed to allow for further skeleton and substituent diversity using click chemistry and urea or amide bond formation. Rapid purification was accomplished using solid-phase extraction. The obtained library comprised 80 molecules incorporating two diversity positions and one chiral center, each of which was efficiently prepared in good purity and acceptable overall yield. A bacterial morphology study was also performed.
Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation
Othman, Raja Ben,Fer, Micka?l J.,Le Corre, Laurent,Calvet-Vitale, Sandrine,Gravier-Pelletier, Christine
, p. 1533 - 1541 (2017)
The 5′-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2′,3′-di-O-protecting groups (R1): O-alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5′R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5′S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.
Evaluation of BBB permeable nucleolipid (NLDPU): A di-C15-ketalised palmitone appended uridine as neuro-tracer for SPECT
Swastika,Chaturvedi, Shubhra,Kaul, Ankur,Hazari, Puja Panwar,Jha, Preeti,Pal, Sunil,Lal, Sangeeta,Singh,Barthélémy, Philippe,Mishra, Anil K.
, p. 269 - 282 (2019)
Despite being in routine for onco-diagnostics for years, the applicability of nucleosidic molecular imaging probes is severely restricted in neurological applications due to their low permeability across blood-brain-barrier (BBB). For extending nucleoside tracers utility for neuro-onco early diagnostics, suitable modification which enhances their BBB permeation needs investigation. Among various modifications, lipidization of nucleosides has been reported to enhance cellular permeability. Extending the concept, the aim was to exemplify the possibility of lipidized nucleosides as potential brain tracer with capability to cross intact BBB and evaluate as metal based neuro-imaging SPECT agent. Uridine based non-lipidic (NSDAU)and di-C15-ketal appended lipidic (NLDPU)ligands were conjugated to chelator, DTPA (DTPA-NSDAU and DTPA-NLDPU)using multi-step chemistry. The ligands were evaluated in parallel for comparative physical and biological parameters. Additionally, effects of enhanced lipophilicity on UV-absorption, acid strength, fluorescence and non-specific protein binding were evaluated. Fluorescence quenching of BSA indicated appreciable interaction of DTPA-NLDPU with protein only above 10 mM without inducing conformational changes. In addition, DTPA-NLDPU was found to be haematocompatible and cytocompatible with low dose-dependent toxicity in HEK-cells. The chelator DTPA was used for 99mTc-complexation for SPECT imaging. Optimized 99mTc-radiolabeling parameters resulted in quantitative (≥97%)labeling with good stability parameters in in-vitro serum and cysteine challenge studies. We demonstrate that the nucleolipid radiotracer (99mTc-DTPA-NLDPU)was successfully able to permeate the BBB with brain uptake of 0.2% ID/g in normal mice as compared to 0.06% ID/g uptake of 99mTc-DTPA-NSDAU at 5 min. Blood kinetics indicate biphasic profile and t1/2(distribution)46 min for 99mTc-DTPA-NLDPU. The preferential accumulation of 99mTc-DTPA-NLDPU in brain tumor intracranial xenograft indicate the targeting capability of the nucleoside. We conclude that as first-of-its-kind, this work presents the potential of the biocompatible nucleolipidic system for brain targeting and early diagnostics.
Photophysical properties of zinc phthalocyanine-uridine single walled carbon nanotube - Conjugates
Ogbodu, Racheal O.,Amuhaya, Edith K.,Mashazi, Philani,Nyokong, Tebello
, p. 231 - 239 (2015)
The photophysical properties of the conjugate of uridine and zinc mono carboxy phenoxy phthalocyanine (ZnMCPPc-uridine, 4) are reported in this work. The conjugate was also adsorbed onto single walled carbon nanotubes (ZnMCPPc-uridine-SWCNT, 5). The X-ray photoelectron spectroscopy of 4 showed three N 1s peaks while that of 5 showed four N 1s peak, a new peak at 399.4 eV of 5 was assigned to pyrrolidonic nitrogen, due to the interaction of the pyrrolic nitrogen of 4 with the oxygen moiety of SWCNT-COOH in 5. The triplet lifetime, triplet and singlet oxygen quantum yields of the zinc mono carboxy phenoxy phthalocyanine increased by over 40% in the presence of uridine. SWCNTs resulted in only a small quenching of the triplet state parameters of 4.
Efficient synthesis and antifungal investigation of nucleosides’ quaternary ammonium salt derivatives
Dmochowska, Barbara,Pellowska-Januszek, Lucyna,Samaszko-Fiertek, Justyna,Slusarz, Rafal,Wakiec, Roland,Madaj, Janusz
, p. 157 - 171 (2019)
Quaternary ammonium salts are a group of compounds with diverse biological properties, the most important of which are their antiviral, antibacterial, and antifungal activities. The quaternization reactions of 5'-O-tosyl derivatives of uridine and thymidine with triethylamine, trimethylamine, 4-(N,N-dimethylamino)pyridine, 2-methylpyridine, and pyridine are described in this article. Two of the synthesized compounds are exceptional because they are first of this type that demonstrate concentration-dependent antifungal in vitro activity against two species of the genus Candida in minimal YNB-SG medium. The experimental results have been extended by adding full atom molecular dynamics simulations and substrates and products energies evaluation.
Selectivity in C-alkylation of dianions of protected 6-methyluridine
Nguyen, Ngoc Hoa,Castanet, Anne-Sophie,Mortier, Jacques,Len, Christophe
, p. 1228 - 1233 (2011)
A regioselective synthesis of 6-ω-alkenyluridines 3, precursors of potent antiviral and antitumor cyclonucleosides 5, is described. While ω-alkenyl halides do not alkylate 6-lithiouridine, compounds 3 were prepared in a regioselective manner by sequential treatment of 6-methyluridine 2 with LTMP or LDA (4 equiv) in THF at ?30 °C followed by alkylation with ω-alkenyl bromides.
A potent, covalent inhibitor of orotidine 5′-monophosphate decarboxylase with antimalarial activity
Bello, Angelica M.,Poduch, Ewa,Fujihashi, Masahiro,Amani, Merhnaz,Li, Yan,Crandall, Ian,Hui, Raymond,Lee, Ping I.,Kain, Kevin C.,Pai, Emil F.,Kotra, Lakshmi P.
, p. 915 - 921 (2007)
Orotidine 5′-monophosphate decarboxylase (ODCase) has evolved to catalyze the decarboxylation of orotidine 5′-monophosphate without any covalent intermediates. Active site residues in ODCase are involved in an extensive hydrogen-bonding network. We discovered that 6-iodouridine 5′-monophosphate (6-iodo-UMP) irreversibly inhibits the catalytic activities of ODCases from Methanobacterium thermoautotrophicum and Plasmodium falciparum. Mass spectral analysis of the enzyme-inhibitor complex confirms covalent attachment of the inhibitor to ODCase accompanied by the loss of two protons and the iodo moiety. The X-ray crystal structure (1.6 ? resolution) of the complex of the inhibitor and ODCase clearly shows the covalent bond formation with the active site Lys-42 residue. 6-Iodo-UMP inhibits ODCase in a time- and concentration-dependent fashion. 6-Iodouridine, the nucleoside form of 6-iodo-UMP, exhibited potent antiplasmodial activity, with IC50S of 4.4 ± 1.3 μM and 6.2 ± 0.7 μM against P. falciparum ItG and 3D7 isolates, respectively. 6-Iodouridine 5′-monophosphate is a novel covalent inhibitor of ODCase, and its nucleoside analogue paves the way to a new class of inhibitors against malaria.
Clay catalyzed acetonation: A simple method for the preparation of isopropylidene carbohydrates
Asakura, Jun-Ichi,Matsubara, Yoshio,Yoshihara, Masakuni
, p. 231 - 239 (1996)
This paper reports a simple method for the preparation of isopropylidene carbohydrates using clay as a catalyst. Treatment of various monosaccharides and/or ribonucleosides with acetone in the presence of clay such as a montmorillonite K 10 (K 10) under mild reaction conditions gave isopropylidene carbohydrates (1-7) in good yields.
Pac13 is a Small, Monomeric Dehydratase that Mediates the Formation of the 3′-Deoxy Nucleoside of Pacidamycins
Michailidou, Freideriki,Chung, Chun-Wa,Brown, Murray J. B.,Bent, Andrew F.,Naismith, James H.,Leavens, William J.,Lynn, Sean M.,Sharma, Sunil V.,Goss, Rebecca J. M.
, p. 12492 - 12497 (2017)
The uridyl peptide antibiotics (UPAs), of which pacidamycin is a member, have a clinically unexploited mode of action and an unusual assembly. Perhaps the most striking feature of these molecules is the biosynthetically unique 3′-deoxyuridine that they share. This moiety is generated by an unusual, small and monomeric dehydratase, Pac13, which catalyses the dehydration of uridine-5′-aldehyde. Here we report the structural characterisation of Pac13 with a series of ligands, and gain insight into the enzyme's mechanism demonstrating that H42 is critical to the enzyme's activity and that the reaction is likely to proceed via an E1cB mechanism. The resemblance of the 3′-deoxy pacidamycin moiety with the synthetic anti-retrovirals, presents a potential opportunity for the utilisation of Pac13 in the biocatalytic generation of antiviral compounds.
Unexpected side product formed during LDA-induced phosphonylation of uridine
Bhar, Palash,Bearne, Stephen L.
, p. 609 - 611 (2017)
The LDA-induced coupling of 2′,3′,5′-O-protected uridine with diethyl chlorophosphate, during the synthesis of 6-phosphonouridine, is accompanied by the formation of an unexpected side product. LDA adds slowly to the C4 position of the 2′,3′,5′-O-protected uridine after the initial reaction with diethyl chlorophosphate. The presence of the phosphorochloridate facilitates the side reaction. This observation accounts for the previously reported low yield when conducting the coupling reaction for longer durations and suggests a new route for the synthesis of N-alkylated 6-phosphonocytidine analogues.
Synthesis and biological evaluation of selective phosphonate-bearing 1,2,3-triazole-linked sialyltransferase inhibitors
Dobie, Christopher,Montgomery, Andrew P.,Skropeta, Danielle,Yu, Haibo,Szabo, Rémi
, p. 1680 - 1689 (2021)
The critical role of sialyltransferase (ST) enzymes in tumour cell growth and metastasis, as well as links to multi-drug and radiation resistance, has seen STs emerge as a target for potential antimetastatic cancer treatments. One promising class of ST inhibitors that improve upon the pharmacokinetic issues of previous inhibitors is the 1,2,3-triazole-linked transition-state analogues. Herein, we present the design and synthesis of a new generation of 1,2,3-triazole-linked sialyltransferase inhibitors, along with their biological evaluation demonstrating increased potency for phosphonate bearing compounds. The six most promising inhibitors presented in this work exhibited a greater number of binding modes for hST6Gal I over hST3Gal I, withKiranging from 3-55 μM. This work highlights phosphonate bearing triazole-linked compounds as a promising class of synthetically accessible ST inhibitors that warrant further investigation.
Propargylglycine-based antimicrobial compounds are targets of TolC-dependent efflux systems in Escherichia coli
Roldan, Bec J.,Pajarillo, Andrea O.,Greenberg, Jacob D.,Karlinsey, Joyce E.,Cafiero, Mauricio,Frawley, Elaine R.,Peterson, Larryn W.
, (2020)
A library of novel L-propargylglycine-based compounds were designed and synthesized with the goal of inhibiting the growth of Gram-negative bacteria by targeting LpxC, a highly conserved Gram-negative enzyme which performs an essential step in the lipid A biosynthetic pathway. These compounds were designed with and without a nucleoside and had varying tail structures, which modulate their lipophilicity. The synthetic scheme was improved compared to previous methods: a methyl ester intermediate was converted to a hydroxamic acid, which obviated the need for a THP protecting group and improved the yields and purity of the final compounds. Antimicrobial activity was observed for non-nucleoside compounds containing a phenyl propargyl ether tail (5) or a biphenyl tail (6). An MIC of 16 μg/mL was achieved for 6 in Escherichia coli, but inhibition was only possible in the absence of TolC-mediated efflux. Compound 5 had an initial MIC >160 μg/mL in E. coli. Enhancing outer membrane permeability or eliminating efflux reduced the MIC modestly to 100 μg/mL and 80 μg/mL, respectively. These results highlight the importance of hydrophobicity of this class of compounds in developing LpxC inhibitors, as well as the design challenge of avoiding multidrug efflux activity.
4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
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Page/Page column 296-297; 351-352; 355-356, (2021/07/10)
Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.
Me3SI-promoted chemoselective deacetylation: a general and mild protocol
Gurawa, Aakanksha,Kashyap, Sudhir,Kumar, Manoj
, p. 19310 - 19315 (2021/06/03)
A Me3SI-mediated simple and efficient protocol for the chemoselective deprotection of acetyl groups has been developedviaemploying KMnO4as an additive. This chemoselective deacetylation is amenable to a wide range of substrates, tolerating diverse and sensitive functional groups in carbohydrates, amino acids, natural products, heterocycles, and general scaffolds. The protocol is attractive because it uses an environmentally benign reagent system to perform quantitative and clean transformations under ambient conditions.
