6554-10-5Relevant academic research and scientific papers
External transesterification of ribonucleotide esters naturally catalyzed by large ribozymes
Roussev, Christo D.,Ivanova, Gabriela D.,Bratovanova, Emilia K.,Vassilev, Nikolay G.,Petkov, Dimiter D.
, p. 11267 - 11272 (1999)
The intriguing chemical mechanism of the external transesterification by which large ribozymes (group I, group II, and spliceosomal introns) splice RNA has been found to operate in the methanolysis of ribonucleoside 2′-/3′-dimethyl phosphates in non-hydrogen-bonding organic solvents. Besides needing aprotic organic media this mechanism requires a high concentration of the attacking alcohol accounting for the binding of an external guanosine by group I introns and the use of a non-adjacent internal 2′-OH by group II and spliceosomal introns. This finding is the first example of an external non-ribozymic transesterification of ribonucleotide esters and the means by which this crucial biochemical reaction can be accelerated.
Glycomimetics Targeting Glycosyltransferases: Synthetic, Computational and Structural Studies of Less-Polar Conjugates
Ghirardello, Mattia,De Las Rivas, Matilde,Lacetera, Alessandra,Delso, Ignacio,Lira-Navarrete, Erandi,Tejero, Tomás,Martín-Santamaría, Sonsoles,Hurtado-Guerrero, Ramón,Merino, Pedro
, p. 7215 - 7224 (2016)
The Leloir donors are nucleotide sugars essential for a variety of glycosyltransferases (GTs) involved in the transfer of a carbohydrate to an acceptor substrate, typically a protein or an oligosaccharide. A series of less-polar nucleotide sugar analogues derived from uridine have been prepared by replacing one phosphate unit with an alkyl chain. The methodology is based on the radical hydrophosphonylation of alkenes, which allows coupling of allyl glycosyl compounds with a phosphate unit suitable for conjugation to uridine. Two of these compounds, the GalNAc and galactose derivatives, were further tested on a model GT, such as GalNAc-T2 (an important GT widely distributed in human tissues), to probe that both compounds bound in the medium-high micromolar range. The crystal structure of GalNAc-T2 with the galactose derivative traps the enzyme in an inactive form; this suggests that compounds only containing the β-phosphate could be efficient ligands for the enzyme. Computational studies with GalNAc-T2 corroborate these findings and provide further insights into the mechanism of the catalytic cycle of this family of enzymes.
Tricyclanos: Conformationally constrained nucleoside analogues with a new heterotricycle obtained from a d-ribofuranose unit
Kicsák, Máté,Mándi, Attila,Varga, Szabolcs,Herczeg, Mihály,Batta, Gyula,Bényei, Attila,Borbás, Anikó,Herczegh, Pál
supporting information, p. 393 - 401 (2018/02/06)
A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.05,11]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl2, Et3SiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.
Synthesis of Nucleosides through Direct Glycosylation of Nucleobases with 5-O-Monoprotected or 5-Modified Ribose: Improved Protocol, Scope, and Mechanism
Downey, A. Michael,Pohl, Radek,Roithová, Jana,Hocek, Michal
supporting information, p. 3910 - 3917 (2017/03/27)
Simplifying access to synthetic nucleosides is of interest due to their widespread use as biochemical or anticancer and antiviral agents. Herein, a direct stereoselective method to access an expansive range of both natural and synthetic nucleosides up to a gram scale, through direct glycosylation of nucleobases with 5-O-tritylribose and other C5-modified ribose derivatives, is discussed in detail. The reaction proceeds through nucleophilic epoxide ring opening of an in situ formed 1,2-anhydrosugar (termed “anhydrose”) under modified Mitsunobu reaction conditions. The scope of the reaction in the synthesis of diverse nucleosides and other 1-substituted riboside derivatives is described. In addition, a mechanistic insight into the formation of this key glycosyl donor intermediate is provided.
In search of flavivirus inhibitors: Evaluation of different tritylated nucleoside analogues
Chatelain, Grégory,Debing, Yannick,De Burghgraeve, Tine,Zmurko, Joanna,Saudi, Milind,Rozenski, Jef,Neyts, Johan,Van Aerschot, Arthur
, p. 249 - 255 (2013/10/01)
Following up on a hit that was identified in a large scale cell-based antiviral screening effort, a series of triphenylmethyl alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against the dengue virus (DENV) and the yellow fever virus (YFV). Hereto, trityl moieties were attached at various positions of the sugar ring combined with subtle variations of the heterocyclic base. Several triphenylmethyl modified nucleosides were uncovered being endowed with submicromolar in vitro antiviral activity against the YFV. The most selective inhibitor in this series was 3′,5′-bis-O-tritylated-5-chlorouridine (1b) affording a selectivity index of over 90, whereas the 3′,5′-bis-O-tritylated inosine congener (5b) displayed the highest activity, but proved more toxic. The finding of these lipophilic structures being endowed with high antiviral activity for flaviviruses, should stimulate the interest for further structureeactivity research.
Synthesis of 3′-azido-4′-ethynyl-3′,5′-dideoxy- 5′-norarabinouridine: A new anti-HIV nucleoside analogue
Amin, Mahmoud A.
scheme or table, p. 1703 - 1708 (2011/04/18)
3′-Azido-4′-ethynyl-3′,5′dideoxy-5′- norarabinouridine 10 was synthesized from commercial uridine 1 in which the key step is the opening of protected 2′,3′-epoxyuridine derivative 7 by sodium azide and the hydroxymethyl at 4-position of the ribose ring are replaced by ethynyl group.
An efficient and selective method for the preparation of triphenylmethyl ethers of alcohols and nucleosides
Zekri, Negar,Alamdari, Reza Fareghi
experimental part, p. 563 - 568 (2010/08/05)
A very simple and efficient method is described for the protection of alcohols and nucleosides with benzyl monomethoxytrityl and benzyl dimethoxytrityl ethers in the presence of diethylazodicarboxylate and a catalytic amount of ceric triflate. High selectivity was observed for the tritylation of 5'-OH function of nucleosides.
A solvent free and selective method for preparation of triphenylmethyl ethers of alcohols and nucleosides
Zekri, Negar,Alamdari, Reza Fareghi,Khalafi-Nezhad, Ali
experimental part, p. 299 - 304 (2012/04/23)
A very simple and efficient method is described for protection of alcohols and nucleosides with trityl(triphenylmethyl), mono and dimethoxytrityl chlorides in the presence of triethylamine under microwave irradiation. High selectivity was observed for tritylation of 5'-OH function of nucleosides.
3′-Bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of mycobacterium tuberculosis
Shakya, Neeraj,Srivastav, Naveen C.,Desroches, Nancy,Agrawal, Babita,Kunimoto, Dennis Y.,Kumar, Rakesh
experimental part, p. 4130 - 4140 (2010/09/04)
Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2′- or 3′-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3′-bromo-3′-deoxy- arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC 50 = 1 μg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC50 = 1-2 μg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 μg/mL concentration) than extracellular mycobacteria (75% reduction at 10 μg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC50 > 100-200 μg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.
Novel selectivity in carbohydrate reactions, IV: DABCO-mediated regioselective primary hydroxyl protection of carbohydrates
Gadakh, Bharat Kacheshwar,Patil, Premanand Ramrao,Malik, Satish,Kartha, K. P. Ravindranathan
experimental part, p. 2430 - 2438 (2009/12/03)
An efficient procedure for the regioselective tritylation of primary hydroxyl group of aldohexopyranosides and nucleosides using trityl chloride in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in dichloromethane has been developed. Subsequent acetylation of the tritylated products in the same pot has been made possible, thereby providing an efficient route to the fully protected carbohydrate derivatives that can be discriminated chemoselectively.
