- Isolation and characterization of two furan-side photoadducts of 7-methylpyrido[3,4-c] psoralen to the sugar moiety of 2′-deoxyadenosine
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The UVA-mediated photoreaction of the monofunctional 7-methylpyrido[3,4-c]psoralen (MePyPs) with 2′-deoxyadenosine was investigated in the dry state. Two main 7-methylpyrido[3,4-c]psoralen monoadducts to 2′-deoxyadenosine were isolated by HPLC and characterized by soft ionization mass spectrometry (fast atom bombardment) and extensive 1H NMR analyses including correlation spectroscopy, total correlation spectroscopy and nuclear Overhauser effect measurements. The two unusual photoadducts exhibit a covalent bond between the C-4′ of the furan moiety of the psoralen on one hand and either the C-1′ or the C-4′ of the furanose ring of the purine nucleoside on the other hand. The furan-side monoadducts appear to be specific for both 2′-deoxyadenosine and MePyPs. They are likely to result from the recombination of the 4′,5′-dihydrofuran-4′-yl radical of MePyPs with 2′-deoxyadenosyl carbon-centered sugar radicals at either the 1′ or the 5′ position.
- Voituriez, Lucienne,Cadet, Jean
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- Synthesis of isomeric analogues of S-ribosylhomocysteine analogues with homocysteine unit attached to C2 of ribose
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LuxS (S-ribosylhomocysteinase; EC 4.4.1.21) is an enzyme that catalyzes the cleavage of the thioether linkage in the catalytic pathway of S-ribosylhomocysteine (SRH) which produces homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD). DPD is the precursor of the signaling molecules known as autoinducer 2 (AI-2) responsible for the bacterial quorum sensing (QS) identified as cell to cell communication. Inhibitors of LuxS should be able to interfere with its catalytic pathway thus preventing the formation of the autoinducer molecules. In this work, the synthesis of 2-deoxy-2-bromo-SRH analogues was attempted by the coupling of the corresponding 2-bromo-2-deoxypentafuranosyl sugars with the homocysteinate anion. The displacement of the bromide from C2 rather than the expected substitution of the mesylate group from C5 was observed leading to a novel isomeric analogue of SRH in which Hcy moiety is attached to a ribose ring via C2-sulfur bond.
- Chbib, Christiane
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- Towards a DNA-like duplex without hydrogen bonds
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The inverse quadrupolar moments of the phenyl and pentafluorophenyl residues in the base pair P-F5 promotes strong intramolecular stacking interactions in DNA duplexes. The more natural base pairs are replaced by this novel pair the higher the thermodynamic stability of the resulting duplex if they are arranged in an alternating fashion.
- Mathis, Gerald,Schuetz, Rolf,Hunziker, Juerg
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- Direct evidence for bimodal DNA damage induced by tirapazamine
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The ability of tirapazamine (1, 3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233) to fix DNA radical lesions is demonstrated by studying the reaction between the antitumor drug and an oligonucleotide radical that is independently produced at a defined site within a biopolymer: Using β- mercaptoethanol as a competitor, it was determined that tirapazamine traps a C1'-nucleotide radical with a rate constant of ~2 x 108 M-1 s-1. Product and isotopic labeling studies suggest that tirapazamine reacts with the radical via covalent adduct formation, resulting primarily from reaction at the N-oxide oxygen. Intermediate covalent adducts could not be observed, but are postulated to decompose to the alkaline labile 2'-deoxyribonolactone lesion. These experiments affirm recent proposals suggesting that tirapazamine can serve as a surrogate for O2 in converting DNA radicals into toxic strand damage events.
- Scott Daniels,Gates, Kent S.,Tronche, Christopher,Greenberg, Marc M.
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- Lanthanide(III) Catalyzed Aldol Reactions of Glyceraldehyde Acetonide with Ketene Silyl Acetals: Catalytic Asymmetric Route to Monosaccharides
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The Pr-, Eu- and Ho(dppm)3 catalyzed aldol reactions of glyceraldehyde acetonide with ketene silyl acetals are described, where remarkably high anti-diastereofacial selection is achieved.Thus, the asymmetric synthesis of 2-deoxy-D-ribonolactone and formal synthesis of 2-amino-2-deoxy-D-pentose by the lanthanide(III) catalyzed aldol reaction with ketene silyl acetals of acetate and α-chloroacetate, respectively are described.
- Mikami, Koichi,Terada, Masahiro,Nakai, Takeshi
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- Fate of the C-1′ peroxyl radical in the 2′-deoxyuridine system
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The mechanism of 2-deoxyribonolactone formation from the reaction of photogenerated 2′-deoxyuridin-1′-yl radical with molecular oxygen in water has been investigated.
- Chatgilialoglu, Chryssostomos,Gimisis, Thanasis
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Read Online
- Hydroxyl-radical-induced decomposition of 2'-deoxycytidine in aerated aqueous solutions
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The stable products resulting from γ-irradiation of 2'-deoxycytidine in aerated aqueous solutions have been purified to homogeneity and characterized by MS and NMR analyses. The main group of products, which are similar in structure to those that arise from the ·OH-mediated decomposition of thymidine, included four diastereomers of 5,6-dihydroxy-5,6-dihydro-2'- deoxyuridine (2-5), 5-hydroxy-2'-deoxycytidine (6), two diastereomers of N1- (2-deoxy-β-D-erythro-pentofuranosyl)-5-hydroxyhydantoin (7 and 8), and N1- (2-deoxy-β-D-erythro-pentofuranosyl)formamide (9). These products are likely formed by way of either intermediate 5(6)-hydroxy-6(5)-peroxyl radicals or the corresponding hydroperoxides. In labeling experiments, 18O2 was incorporated into products 2-9 with about 30% label at C5 and 60% at C6. Several other products were observed in the γ-irradiation of 2'- deoxycytidine in aerated aqueous solutions. They included four isomeric nucleosides of biuret (10-13), two diastereomers of N1-(2-deoxy-β-D- erythro-pentofuranosyl)-1-carbamoyl-2-oxo-4,5-dihydroxyimidazoline (14, 15), and aminocarbonyl[2-(2-deoxy-β-D-erythro-pentofuranosyl)amino]-2-oxo- ethylcarbamic acid (16). The first step in the formation of these products is probably intramolecular addition of the 5-hydroxy-6-hydroperoxide to C4 of the pyrimidine ring, resulting in a 4,6-endoperoxide which decomposes into an open-chain α-hydroxyaldehyde by C4-C5 cleavage. The formation of products 10-13 can be explained by subsequent fragmentation of the intermediate α- hydroxyaldehyde, whereas cyclization gives rise to products 14 and 15. In the case of products 16, a series of reactions have been proposed, starting with the rearrangement of the α-hydroxyaldehyde. The above pathways are supported by 18O2-labeling experiments. Finally, we characterized two diastereomers of 5',6-cyclo-5-hydroxy-5,6-dihydro-2'-deoxyuridine(17,81) in the γ- irradiation of 2'-deoxycytidine in aerated aqueous solutions. These products likely arise from initial ·OH abstraction of a proton from C(5') of the sugar moiety, followed by intramolecular addition of the resulting radical to C6 of the cytosine moiety. The ·OH-mediated decomposition of 2'- deoxycytidine in DNA is discussed.
- Wagner, J. Richard,Decarroz, Chantal,Berger, Maurice,Cadet, Jean
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- Short synthesis of (3S,4R)- and (3R,4R)-3-hydroxy-4-hydroxymethyl-4-butanolides, two lactones from levoglucosenone
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Two lactones, (3S,4R)- and (3R,4R)-3-hydroxy-4-hydroxymethyl-4-butanolides, were easily and stereoselectively synthesized in good yield from levoglucosenone (1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose).
- Matsumoto,Ebata,Koseki,Okano,Kawakami,Matsushita
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- Homochiral 4-hydroxy-5-hexenoic acids and their derivatives and homologues from carbohydrates
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Efficient routes to chiral 4-hydroxy-5-hexenoic acids and lactones from D-gluconic acid-δ-lactone and L-mannonic acid-γ-lactone are described. In this approach, the starting lactones are converted to 2,6-dibromo compounds that readily undergo zinc mediated elimination to generate the terminal alkene group in concert with 2-deoxygenation. The integrity of the remaining stereocenters is preserved during the reaction. The related important pharmaceutical intermediates (S)-3-hydroxy-4-pentenoic acid and (S)-1,3-dihydroxy-4-pentene were also prepared from 2-deoxyribose via the corresponding aldonolactone.
- Song, Jie,Hollingsworth, Rawle I.
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- CYCLOPENTYL NUCLEOSIDE ANALOGS AS ANTI-VIRALS
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Described herein are cyclopentyl nucleoside analogs, pharmaceutical compositions that include one or more cyclopentyl nucleoside analogs and methods of using the same to treat HBV, HDV and/or HIV.
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Paragraph 0300
(2020/07/07)
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- METHOD FOR PRODUCING SUGAR
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PROBLEM TO BE SOLVED: To provide a method for conveniently producing useful sugar. SOLUTION: There is provided a method whereby a basic aqueous solution of predetermined sugar is irradiated with ultraviolet rays in the presence of ketone, to produce isomerized sugar. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0047
(2020/10/21)
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- Intercepted dehomologation of aldoses by N-heterocyclic carbene catalysis-a novel transformation in carbohydrate chemistry
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The development of an N-heterocyclic carbene (NHC) catalysed intercepted dehomologation of aldoses is reported. The unique selectivity of NHCs for aldehydes is exploited in the complex context of reducing sugars. Examples of strong substrate governance for either intercepted dehomologation or a subsequent redox-lactonisation were identified and mechanistically understood. More importantly, it was shown that catalyst design allowed the tuning of the selectivity of the reaction with structurally unbiased starting materials towards either of the two scenarios.
- Draskovits, Markus,Kalaus, Hubert,Stanetty, Christian,Mihovilovic, Marko D.
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p. 12144 - 12147
(2019/10/21)
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- Light Regulation of DNA Minicircle Dimerization by Utilizing Azobenzene C-Nucleosides
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Although DNA has the ability to form almost every desired shape, the usability of DNA nanostructures can be limited due to the lack of functionality. To functionalize nanoscale structures, light-responsive moieties like photoswitchable azobenzenes can be introduced into DNA. Upon UV irradiation, the isomerization of the azobenzene moiety causes destabilization of the neighboring base pairs leading to decreased binding ability. The linker strategy of the azobenzene to the DNA alters the performance of the switching behavior significantly. We hereby report the utilization of four different azobenzene C-nucleosides and compare their features in a nanoarchitecture model with the help of gel-electrophoresis and atomic force microscope-imaging.
- Grebenovsky, Nikolai,Goldau, Thomas,Bolte, Michael,Heckel, Alexander
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supporting information
p. 3425 - 3428
(2018/02/15)
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- 2′-Chloro,2′-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture
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Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2′-Cl,2′-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5′-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.
- Zhou, Shaoman,Mahmoud, Sawsan,Liu, Peng,Zhou, Longhu,Ehteshami, Maryam,Bassit, Leda,Tao, Sijia,Domaoal, Robert A.,Sari, Ozkan,Schutter, Coralie De,Amiralaei, Sheida,Khalil, Ahmed,Ollinger Russell, Olivia,McBrayer, Tamara,Whitaker, Tony,Abou-Taleb, Nageh,Amblard, Franck,Coats, Steven J.,Schinazi, Raymond F.
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p. 5424 - 5437
(2017/07/22)
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- Nucleotide phosphoramidate formulation
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Compound 1 with the formula I is an HCV antiviral protide, which is surprisingly soluble in ethanol, thereby facilitating the preparation of pharmaceutical formulations, such as adsorbed mesoporous carriers or SEDDS of Pouton Types III or IV.
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Paragraph 0168; 0169; 0170; 0171; 0172
(2017/12/27)
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- Anti-Viral Compounds
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The present invention features compounds effective in inhibiting active against Hepatitis C virus (“HCV”) polymerase. The invention also features processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.
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Paragraph 0268; 0269; 0320; 0321
(2017/03/21)
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- METHODS FOR THE PREPARATION OF DIASTEREOMERICALLY PURE PHOSPHORAMIDATE PRODRUGS
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Methods for the preparation of diastereomerically pure phosphoramidate prodrugs of nucleosides, and intermediates useful for the preparation are provided. The nucleosides are useful for the treatment of hepatitis C and cancer.
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Page/Page column 90
(2016/04/09)
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- 2' -DISUBSTITUTED NUCLEOSIDE ANALOGS FOR TREATMENT OF THE FLAVIVIRIDAE FAMILY OF VIRUSES AND CANCER
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The present invention is directed to compounds, compositions and methods for treating or preventing Flaviviridae family of viruses (including HCV, Yellow fever, Dengue, Chikungunya and West Nile virus), RSV and influenza infection and cancer in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof as pharmaceutical compositions and methods for treatment or prevention of HCV infection.
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Page/Page column 64
(2015/11/16)
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- Stereoselective Allylstannane Addition for a Convergent Synthesis of a Complex Molecule
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A convergent methodology with 13 lineal steps for the synthesis of phormidolides B and C macrocyclic core is described. Stereoselective formation of the tetrahydrofuran (THF) core was achieved using a stereocontrolled allylation reaction. The key step of the synthesis is a (Z)-1,5-anti stereoselective allylstannane addition where a new stereocenter and a trisubstituted double bond are formed simultaneously. Finally, Shiina macrolactonization conditions improved the yield of the final cyclization.
- Gil, Alejandro,Lorente, Adriana,Albericio, Fernando,álvarez, Mercedes
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p. 6246 - 6249
(2016/01/09)
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- 2'-DICHLORO AND 2'-FLUORO-2'-CHLORO NUCLEOSIDE ANALOGUES FOR HCV INFECTION
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Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are 2'-dichloro or 2'-fluoro-2'-chloro nucleoside analogue compounds which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the compounds are of Formula (I):or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof; wherein each of RA and RB is independently Cl or F, wherein at least one of RA and RB is C1; and Base, PD and Z are as described herein.
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Paragraph 00291
(2015/06/11)
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- Synthesis of C-spiro-glycoconjugates from sugar lactones via zinc mediated Barbier reaction
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Anomeric gem-diallylation, mono-β-crotylation and mono-β- propargylation of sugar 1,5 and 1,4 lactones have been achieved under Barbier reaction conditions using Zn powder and a catalytic amount of TMSCl as an activator. Ring closing olefin metathesis of the synthesized gem-diallyl derivatives furnished C-spiro cyclopentene glycosides. Finally, the cyclopentene rings were converted into carbohydrate based tricyclic morpholine fused triazole glycoconjugates as potential SGLT2 inhibitors.
- Lambu, Mallikharjuna Rao,Hussain, Altaf,Sharma, Deepak K.,Yousuf, Syed Khalid,Singh, Baldev,Tripathi, Anil. K.,Mukherjee, Debaraj
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p. 11023 - 11028
(2014/03/21)
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- Nucleophilic addition to silyl-protected five-membered ring oxocarbenium ions governed by stereoelectronic effects
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A series of fused-bicyclic acetals containing a disiloxane ring was investigated to evaluate the source of selectivity in silyl-protected 2-deoxyribose systems. The disiloxane ring unexpectedly enables the diaxial conformer of the cation to be stabilized by an electronegative atom at C-3. This low energy conformer subsequently undergoes stereoelectronically controlled nucleophilic addition to give substituted tetrahydrofurans with high diastereoselectivity.
- Tran, Vi Tuong,Woerpel
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p. 6609 - 6621
(2013/07/26)
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- Complementary and stereodivergent approaches to the synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids from enantiopure hydroxylated lactams
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We describe two complementary and stereodivergent routes, from commercially available and inexpensive starting materials, for the synthesis of 4,5-dihydroxy- and 5-hydroxypipecolic acids based on the chemistry of lactam-derived enol phosphates. The synthesis of the 4,5-cis-4,5- dihydroxypipecolic acids required the preparation from 2-deoxy-D- and -L-ribose of the enantiopure cis-(4S,5R)- and -(4R,5S)-4,5-dihydroxy-δ-valerolactam, respectively. These new chiral synthons are potentially useful for the synthesis of other natural products. The key step is the Pd-catalyzed methoxycarbonylation reaction of the enol phosphates generated from these lactams. This reaction provided enecarbamate esters that were easily converted by stereoselective reduction to the target compounds. The synthesis of the 4,5-trans-4,5-dihydroxypipecolic acid, as well as of 5-hydroxypipecolic acids, was realized from a known (S)-5-hydroxy-δ-valerolactam derivative and, for the dihydroxylated compound, required a highly stereoselective allylic bromination reaction of the enecarbamate ester obtained by methoxycarbonylation of the enol phosphate. The preparation of the (4R,5S) enantiomer of the cis-4,5-dihydroxy-δ-valerolactam from 2-deoxy-L-ribose, alongside the fact that (R)-5-hydroxy-δ-valerolactam can be prepared from (R)-(-)-γ-hydroxymethyl-γ-butyrolactone, means our approach allows for the synthesis of all stereoisomers of these compounds, which can be employed as conformationally constrained scaffolds in drug discovery. The stereoselective synthesis of 5-hydroxy- and 4,5-dihydroxypipecolic acids was accomplished by sequential Pd-catalysed methoxycarbonylation and stereoselective reduction of enantiopure hydroxylated lactam-derived enol phosphates obtained from both enantiomers of commercially available γ-hydroxymethyl-γ- butyrolactone and 2-deoxyribose. Copyright
- Scarpi, Dina,Bartali, Laura,Casini, Andrea,Occhiato, Ernesto G.
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p. 1306 - 1317
(2013/04/10)
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- Histone-catalyzed cleavage of nucleosomal DNA containing 2-deoxyribonolactone
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Oxidized abasic sites such as 2-deoxyribonolactone (L) are produced in DNA by a variety of oxidizing agents, including potent cytotoxic antitumor natural products. 2-Deoxyribonolactone is labile under alkaline conditions, but its half-life in free DNA at pH 7.5 is approximately 1 week. Independent generation of L at defined positions within nucleosomes reveals that the histone proteins catalyze strand scission and increase the rate between 11- and ～43-fold. Mechanistic studies indicate that DNA-protein cross-links are not intermediates en route to strand scission and that C2 deprotonation is the rate-determining step. The use of mutant histone H4 proteins demonstrates that the lysine-rich tail that is often post-translationally modified in cells contributes to the cleavage of L but is not the sole source of the enhanced cleavage rates. Consideration of DNA repair in cells suggests that L formation in nucleosomal DNA as part of bistranded lesions by antitumor antibiotics results in de facto double strand breaks, the most deleterious form of DNA damage.
- Zhou, Chuanzheng,Greenberg, Marc M.
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supporting information; experimental part
p. 8090 - 8093
(2012/07/14)
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- Dihydroxylation-based approach for the asymmetric syntheses of hydroxy-γ-butyrolactones
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A method of preparing enantiopure hydroxy-γ-butyrolactones containing multiple contiguous stereocenters in high yield with good diastereoselectivity has been developed. Osmium tetroxide mediated dihydroxylation of a range of β-alkenyl-β-hydroxy-N-acyloxazolidin-2-ones results in formation of triols that undergo spontaneous intramolecular 5-exo-trig cyclization reactions to provide hydroxy-γ-butyrolactones. The stereochemistry of these hydroxy-γ-butyrolactones has been established using NOE spectroscopy, which revealed that 1-substituted, 1,1-disubstituted, (E)-1,2-disubstituted, (Z)-1,2-disubstituted, and 1,1,2-trisubstituted alkenes undergo dihydroxylation with anti-diastereoselectivity, while 1,2,2-trisubstituted systems afford syn-diastereoisomers. The synthetic utility of this methodology has been demonstrated for the asymmetric synthesis of the natural product 2-deoxy-d-ribonolactone. Published 2011 by the American Chemical Society.
- Peed, Jennifer,Davies, Iwan R.,Peacock, Lucy R.,Taylor, James E.,Kociok-Koehn, Gabriele,Bull, Steven D.
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p. 543 - 555
(2012/02/04)
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- Organocatalytic conversion of ribose and other protected carbohydrate derivatives into 2-deoxy-lactones
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We report the simultaneous reduction of the 2-position and oxidation of the anomeric position in several protected furanosyl and pyranosyl sugar derivatives, mediated through NHC catalysis. This reaction allows the one-step access to highly valuable 2-deoxy-sugars from abundant 2-oxygenated sugar derivatives. Georg Thieme Verlag Stuttgart · New York.
- Wendeborn, Sebastian,Mondière, Régis,Keller, Isabelle,Nussbaumer, Hannes
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scheme or table
p. 541 - 544
(2012/04/04)
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- Role of pseudoephedrine as chiral auxiliary in the "acetate-Type" aldol reaction with chiral aldehydes; Asymmetric synthesis of highly functionalized chiral building blocks
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We have studied in depth the aldol reaction between acetamide enolates and chiral α-heterosubstituted aldehydes using pseudoephedrine as chiral auxiliary under double stereodifferentiation conditions, showing that high diastereoselectivities can only be achieved under the matched combination of reagents and provided that the α-heteroatom-containing substituent of the chiral aldehyde is conveniently protected. Moreover, the obtained highly functionalized aldols have been employed as very useful starting materials for the stereocontrolled preparation of other interesting compounds and chiral building blocks such as pyrrolidines, indolizidines, and densely functionalized β-hydroxy and β-amino ketones using simple and high-yielding methodologies.
- Ocejo, Marta,Carrillo, Luisa,Vicario, Jose L.,Badia, Dolores,Reyes, Efraim
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experimental part
p. 460 - 470
(2011/04/12)
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- HALOGENATED 2-DEOXY-LACTONES, 2'-DEOXY--NUCLEOSIDES, AND DERIVATIVES THEREOF
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Disclosed are halogenated 2-deoxy-lactone, 2'-deoxy-nucleosides, and derivatives thereof, for example, a compound of formula (I). Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one compound or salt of the invention, and a method of treating a disorder is selected from the group consisting of an abnormal cellular proliferation, a viral infection, and an autoimmune disorder.
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Page/Page column 40-41
(2011/02/24)
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- Diastereocontrolled electrophilic fluorinations of 2-deoxyribonolactone: Syntheses of all corresponding 2-deoxy-2-fluorolactones and 2′-deoxy- 2′-fluoro-NAD+s
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(Chemical Equation Presented) Methods to construct 2′-deoxy-2′- fluoro nucleosides have undergone limited improvement in the last 20 years in spite of the substantially increased value of these compounds as pharmaceuticals and as tools for studying biological processes.We herein describe a consolidated approach to synthesize precursors to these commercially and scientifically valuable compounds via diastereocontrolled fluorination of the readily available precursor 2-deoxy-D-ribonolactone.With employment of appropriate sterically bulky silyl protecting groups at the 3 and 5 positions, controlled electrophilic fluorination of the Liribonolactone enolate by N-fluorodibenzenesulfonamide yielded the corresponding 2-deoxy-2- fluoroarabinolactone in high isolated yield (72%). The protected 2-deoxy-2,2-difluororibonolactone was obtained similarly in high yield from a second round of electrophilic fluorination (two steps, 51%from protected ribonolactone starting material). Accomplishment of the difficult ribofluorination of the lactone was achieved by the directive effects of a diastereoselectively installed α-trimethylsilyl group. Electrophilic fluorination of a protected 2-deoxy-2-trimethylsilylarabinolactone via enolate generation provided the protected 2-deoxy-2-fluororibolactone as the exclusive fluorinated product. The reaction also yielded the starting material, the desilylated protected 2-deoxyribonolactone, which was recycled to provide a 38%chemical yield of the fluorinated product (versus initial protected ribonolactone) after consecutive silylation and fluorination cycles.Using our fluorinated sugar precursors, we prepared the 2′-fluoroarabino-, 2′-fluororibo-, and 2′,2′-difluoronicotinamide adenine dinucleotides (NAD+) of potential biological interest. These syntheses provide the most consolidated and efficient methods for production of sugar precursors of 2′-deoxy-2′-fluoronucleosides and have the advantage of utilizing an air-stable electrophilic fluorinating agent. The fluorinated NAD+s are anticipated to be useful for studying a variety of cellular metabolic and signaling processes.
- Cen, Yana,Sauve, Anthony A.
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experimental part
p. 5779 - 5789
(2010/01/06)
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- Direct and facile syntheses of heterocyclic vinyl-C-nucleosides for recognition of inverted base pairs by DNA triple helix formation: First report by direct Wittig route
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(Chemical Equation Presented) The ability to recognize specific gene sequences canonically would allow precise means for genetic intervention. However, specific recognition of two of the four possible base pairs by triplex-forming oligonucleotides (TFO) as X·T-A and Y·C-G within a triplex currently remains elusive. A series of C1-vinyl nucleosides have been proposed, and their stability and specificity have been evaluated extensively by molecular dynamics simulation. Because most C-nucleoside syntheses extend through direct substitution at the C1-position, a more convenient strategy for their syntheses via a direct Wittig coupling is presented here.
- Rothman, Jeffrey H.
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p. 3945 - 3948
(2008/02/01)
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- New modular and efficient approach to 6-substituted pyridin-2-yl C-nucleosides
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A novel modular, efficient, and practical methodology of preparation of 6-substituted pyridin-2-yl C-nucleosides was developed. An addition of 2-lithio-6-bromopyridine 2b to TBDMS-protected 2-deoxyribonolactone 5 gave aduct 7 as an equilibrium mixture of anomeric hemiketals 1-(6-bromopyridin-2-yl)-1- hydroxynucleosides 7a,b and its open form 7c. Reduction of the adduct 7 with Et3SiH and BF3-Et2O afforded the desired 6-bromonucleoside 8a as pure β-anomer in a total yield of 32% over two steps from 5. Intermediate 8a was then subjected to a series of palladium catalyzed cross-coupling reactions and aminations to give a series of protected 1β-(6-alkyl-, 6-aryl-, and 6-aminopyridin-2-yl)-2-deoxyribonucleosides 9. Catalytic hydrogenation of 8a gave an unsubstituted pyridine C-nucleoside, and diazotative oxodeamination of 6-aminopyridine nucleoside 9f by isopentyl nitrite in acetic acid gave 6-oxopyridine nucleoside 10i. Deprotection of silylated nucleosides 9 by Et3N-SHF gave a series of free C-nucleosides 10.
- Urban, Milan,Pohl, Radek,Klepetarova, Blanka,Hocek, Michal
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p. 7322 - 7328
(2007/10/03)
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- Synthesis of functionalized biphenyl-C-nucleosides and their incorporation into oligodeoxynucleotides
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We describe the synthesis of eight novel C-nucleosides in which the nucleobases are replaced by biphenyl residues that carry one or two electron donor (-OCH3, -NH2) or acceptor (-NO2) functional groups in the distal ring. These C-nucleosides were synthesized convergently and in high yields from a common bromophenyl-C-nucleoside precursor via Suzuki coupling with the respective boronic acids or esters. These nucleosides were subsequently converted into the corresponding phosphoramidite building blocks and efficiently incorporated into oligodeoxynucleotides by standard phosphoramidite chemistry.
- Zahn, Alain,Leumann, Christian J.
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p. 6174 - 6188
(2007/10/03)
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- Novel gluconate dehydratase
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A novel gluconate dehydratase derived from Achromobacter xylosoxidans and a gene encoding the gluconate dehydratase are provided. By reacting the gluconate dehydratase or a transformed cell containing the gene with an aldonic acid, the corresponding 2-keto-3-deoxyaldonic acid can be efficiently produced.
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- A set of nonpolar thymidine nucleoside analogues with gradually increasing size
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(Chemical Equation Presented) We describe a series of nonpolar nucleoside analogues having similar shapes and gradually increasing size. The structure of the nucleobase thymine was mimicked with toluene derivatives, replacing 02/04 with hydrogen, fluorine, chlorine, bromine, and iodine. Glycosidic bonds were formed by reactions of lithiated 2,4-dihalotoluenes with a deoxyribonolactone derivative. Structural analysis by NMR showed similar conformations across the series. The compounds are useful for study of the biological recognition of nucleotides and nucleic acids.
- Tae, Woo Kim,Kool, Eric T.
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p. 3949 - 3952
(2007/10/03)
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- Enantioselective Synthesis and Biological Activity of (3S,4R)- and (3S,4S)-3-Hydroxy-4-hydroxymethyl-4-butanolides in Relation to PGE2
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Compounds 9 and 13 were synthesized, and their structures and stereochemistry were elucidated by spectroscopic methods. In competition binding experiments, specific [3H]-PGE2 binding was significantly displaced by compound 9 and, to a lesser extent, by 13, in a dose-dependent manner. The biological properties of compound 9 were studied on HL-60 cells, and several effects were found related to those of PGE 2. Compound 9 increases c-fos mRNA level as does PGE2 and antagonizes TPA-induced terminal differentiation.
- Miranda, Pedro O.,Estévez, Francisco,Quintana, José,Garcia, Candelaria I.,Brouard, Ignacio,Padrón, Juan I.,Pivel, Juan P.,Bermejo, Jaime
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p. 292 - 295
(2007/10/03)
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- Syntheses of 4-[1-(2-deoxy-β-D-ribofuranosyl)]-derivatives of 2-substituted-5-fluoroaniline: 'Cytosine replacement' analogs of deoxycytidine for evaluation as anticancer and antihuman immunodeficiency virus (anti-HIV) agents
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A group of 4-[1-(2-deoxy-β-D-ribofuranosyl)]-derivatives of 5-fluoroaniline possessing a variety of aryl C-2 substituents (6a R = H, 6b R = F, 6c R = Me) were synthesized. Accordingly, a Heck-type coupling reaction of the 4-iodoaniline derivatives (13a-c) with the bis(tert-butyldimethylsilyl)glycal (11) in the presence of Pd(OAc)2 and Ph3As, followed by removal of the tert-butyldimethylsilyl protection groups using n-Bu4N+F-, yielded the corresponding 4-(β-D-glycero-pentofuran-3-ulos-1-yl)aniline derivatives (14a-c) having a C-3 C=O in the sugar ring. Reduction of the C-3 C=O compounds (14a-c) using NaB(OAc)3H afforded the target 4-[1-(2-deoxy-β-D-ribofuranosyl)]-derivatives of the respective 2-substituted-5-fluoroaniline (6a-c). The deoxycytidine mimic, 3-fluoro-4-[1-(2-deoxy-β-D-ribofuranosyl)]aniline (6a), in which the cytosine ring of deoxycytidine is replaced by a 4-(3-fluoroaniline) ring system, was inactive as an anticancer agent against a variety of tumor cell lines, and as an antihuman immunodeficiency virus (HIV-1, HIV-2) agent. The failure of this unnatural deoxycytidine mimic (6a) to exhibit anticancer-antiviral activity may be due to its inability to undergo phosphorylation by host cell- and virus-induced kinases.
- Wang,Wiebe,De Clercq,Balzarini,Knaus
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p. 1081 - 1088
(2007/10/03)
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- The 7-nitroindole nucleoside as a photochemical precursor of 2′-deoxyribonolactone: Access to DNA fragments containing this oxidative abasic lesion
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On the basis of molecular modeling studies, the 7-nitroindole nucleoside 1 was selected as a suitable photochemical precursor for photochemical generation of the C1′ deoxyribosyl radical under irradiation, which led to 2′-deoxyribonolactone. The nitroindole nucleoside derivatives 1a and 1b were prepared and their conformation was determined by X-ray crystallography and NMR spectroscopy. The photoreaction of these nucleosides gave the corresponding deoxyribonolactone derivatives efficiently, with release of 7-nitrosoindole. This reaction was successfully applied to synthesis of oligonucleotides containing the deoxyribonolactone lesion.
- Kotera, Mitsuharu,Roupioz, Yoann,Defrancq, Eric,Bourdat, Anne-Gaelle,Garcia, Julian,Coulombeau, Christian,Lhomme, Jean
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p. 4163 - 4169
(2007/10/03)
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- Disiloxane-protected 2-deoxyribonolactone as an efficient precursor to 1,2-dideoxy-1-β-aryl-D-ribofuranoses
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(matric presented) Aryl C-nucleosides are analogues of natural nucleosides where the bases have been replaced with aromatic moieties. Work herein describes the highly stereoselective syntheses of non-hydrogen-bonding carbocyclic derivatives using a disiloxane-protected 2-deoxy-D-ribono-1,4-lactone as a stable and readily accessible starting material. Unlike the bis(TBDMS)-protected congener, this compound enables the use of sterically congested ortho-substituted aryllithium reagents in the initial addition reaction.
- Wichai, Uthai,Woski, Stephen A.
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p. 1173 - 1175
(2008/02/09)
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- Chiral synthesis of (S)-(+)-γ-hydroxymethyl-γ-butyrolactone
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S-(+)-γ-hydroxymethyl-γ-butyrolactone has been synthesized from D- ribonolactone as chiral template.
- Salas-Reyes
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p. 2187 - 2199
(2007/10/03)
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- Efficient chemical synthesis of oligonucleotides containing the 2- deoxyribonolactone site
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A highly efficient synthetic method for incorporation of the deoxyribonolactone lesion into oligonucleotides was developed using the photochemical properties of 7-nitroindole.
- Kotera, Mitsuharu,Bourdat, Anne-Gaelle,Defrancq, Eric,Jourdan, Muriel,Garcia, Julian,Coulombeau, Christian,Lhomme, Jean
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p. 1323 - 1324
(2007/10/03)
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- An improved route to 1,2-dideoxy-β-1-phenyl-D-ribofuranose
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An efficient synthesis of the aryl nucleoside analogue 1,2-dideoxy-β- 1-phenyl-D-ribofuranose (1) is described. This route utilizes the addition of phenyllithium to a protected 2-deoxyribonolactone followed by reduction with triethylsilane/boron trifluoride etherate to selectively produce the β- anomer. Deprotection yields the desired aryl C-nucleoside in 27% overall yield from 2-deoxy-D-ribose.
- Wichai, Uthai,Woski, Stephen A.
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p. 3465 - 3468
(2007/10/03)
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- Direct effect of heavy ions and electrons on 2′-deoxyguanosine in the solid state
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Attempts have been made in this work to gain insights into the mechanisms of the formation of degradation products arising from the exposure of 2′-deoxyguanosine (dGuo) in the solid state to O7+ heavy ions of 10.6 MeV u-1 (LET ≈ 500 keV μm-1). The main decomposition products of dGuo have been isolated by reversed-phase high performance liquid chromatography and characterized by extensive spectroscopic (1H and 13C NMR, mass spectrometry, UV) measurements. Reaction mechanisms, involving the transient formation of sugar and purine radical, are proposed to explain the generation of the heavy ion-mediated degradation products. Another major objective of the present work is the comparison of heavy ion-induced modifications of 2′-deoxyguanosine with those produced by lower LET radiation. For this purpose, the samples of 2′-deoxyguanosine were exposed in the solid state to electrons of 2 MeV (LET ≈ 0.18 keV μm-1). It may be inferred from the results of the qualitative and semi-quantitative comparison that the modifications of the sugar moiety are more efficiently induced by heavy ions than by electrons.
- Gromova, Marina,Nardin, Robert,Cadet, Jean
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p. 1365 - 1374
(2007/10/03)
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- Stereocontrol in organic synthesis using silicon-containing compounds. Syntheses of (±)-2-deoxyribonolactone and (±)-arabonolactone
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Samarium iodide reacts with methyl (Z)-3-dimethyl(4-methylphenyl)silylprop-2-enoate 5b to give dimethyl (3RS,4SR)-3,4-bis[dimethyl(4-methylphenyl)silyl]hexane-1,6-dioate 8b with high stereoselectivity. This meso diester can be converted into (3RS,4SR)-3,4-bis[dimethyl(4-methylphenyl)silyl]pentan-5-olide 16 by Dieckmann cyclisation, demethoxycarbonylation and Baeyer-Villiger reaction. Silyl-to-hydroxy conversion and relactonisation gave (±)-deoxyribonolactone, and anti-selective enolate hydroxylation followed by silyl-to-hydroxy conversion gave (±)-arabonolactone. An attempt to synthesise sugars with the relative configuration (3RS,4RS) was thwarted by an unprecedented retention of configuration at the migration origin in the cationic rearrangement of (3RS,4SR)-3,4-bis[dimethyl(4-methylphenyl)silyl]-5-hydroxypentanoic acid 28 to (3RS,4SR)-3,5-bis[dimethyl(4-methylphenyl)silyl]pentan-1,4-olide 30.
- Fleming, Ian,Ghosh, Sunil K.
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p. 2711 - 2720
(2007/10/03)
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- Kinetics and mechanism of the oxidation of sugars and nucleotides by oxoruthenium(IV): Model studies for predicting cleavage patterns in polymeric DNA and RNA
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Kinetic parameters for the oxidation of D-ribose, 2-deoxy-D-ribose, adenosine 5'-monophosphate (AMP), adenosine 5'-diphosphate (ADP), 2'-deoxyadenosine 5'-monophosphate (dAMP), cytidine 5'-monophosphate (CMP), 2'-deoxycytidine 5'-monophosphate (dCMP), and thymidine 5'-monophosphate (TMP) by Ru(tpy)(bpy)O2+ were determined in pH 7 phosphate buffer (tpy = 2,2',2''-terpyridine, bpy = 2,2'-bipyridine). Plots of k(obs) vs [substrate] were linear for the oxidation of ribose, 2-deoxyribose, TMP, and dCMP, yielding second-order rate constants of 0.029, 0.082, 0.38, and 0.46 M-1 s-1, respectively. From the temperature dependence of the rate constant, activation parameters consistent with the oxidation of other organic molecules by hydride transfer were found. For GMP, AMP, and dAMP, k(obs) vs [substrate] plots were curved due to electrostatic binding of Ru(tpy)(bpy)O2+ to the dianionic nucleotides, and the data were treated using double-reciprocal plots, yielding effective second-order rate constants of 0.10, 0.39, and 2.5 M-1 s-1, respectively. Product analysis by HPLC shows that a quantitative yield of free cytosine is obtained upon oxidation of dCMP based on nucleotide consumed. In TMP oxidations, an 80% yield of free thymine is observed based on Ru(tpy)(bpy)O2+ consumed. The kinetics and product analyses are consistent with sugar oxidation at the 1' position, and the increased reactivity of DNA compared to RNA can be understood on the basis of deactivation of the sugar oxidation product by the polar effect of the 2'-hydroxyl. The oxidation of the guanine base in GMP by Ru(tpy)(bpy)O2+ proceeds via an oxo transfer mechanism where the initial step is formation of a bound Ru(III)OR2+ intermediate. The ratio of the rate-determining rate constant for oxidation of guanine nucleotides to the average rate constant of sugar oxidation predicts the relative yields of base and sugar oxidation on sequencing gels.
- Neyhart,Cheng,Thorp
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p. 1463 - 1471
(2007/10/02)
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- A NEW AND DIRECT ACCESS TO GLYCONO-1,4-LACTONES FROM GLYCOPYRANOSES BY REGIOSELECTIVE OXIDATION AND SUBSEQUENT RING RESTRICTION
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Treatment of partially protected or unprotected carbohydrates with the RhH(PPh3)4-benzalacetone system leads exclusively to glycono-1,4-lactones by regioselective oxidation and subsequent ring restriction.
- Isaac, Isabelle,Stasik, Imane,Beaupere, Daniel,Uzan, Raoul
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p. 383 - 386
(2007/10/02)
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- SYNTHESIS OF 2-DEOXYXYLOLACTONE FROM GLYCEROL DERIVATIVES VIA HIGHLY ENANTIOSELECTIVE CARBON-HYDROGEN INSERTION REACTIONS
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diazodecomposition of 1,3-dialkoxy-2-propyl diazoacetates catalyzed by chiral dirhodium(II) carboxamides results in highly enantioselective and diastereoseelctive carbon-hydrogen insertion which forms 3,5-dialkyl 2-deoxyxylolactones in up to 98percent enantiomeric excess.
- Doyle, Michael P.,Dyatkin, Alexey B.,Tedrow, Jason S.
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p. 3853 - 3856
(2007/10/02)
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- Investigations of the Formation of Cyclic Acetal and Ketal Derivatives of D-Ribono-1,4-lactone and 2-Deoxy-D-ribono-1,4-lactone
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The reactions of D-ribono-1,4-lactone, and 2-deoxy-D-ribono-1,4-lactone with benzaldehyde and acetone in acidic media were investigated.The products obtained were isolated and characterized.The 1H NMR spectra of the 1,5-lactone product resulting from the thermodynamically controlled reaction of D-ribono-1,4-lactone with benzaldehyde were examined between 300 K and 200 K in a polar solvent.No conformational changes in the 1,5-lactone ring were observed within this temperature range.Detailed NMR studies showed that the acetalization of D-ribono-1,4-lactoneproceeded with the initial formation of the endo-2,3-acetal derivative, which in the presence of aqueous acids underwent ring expansion and isomerization to the 3,4-acetal of the 1,5-lactone.The endo preference of benzylidene acetals was explained by the transition state conformation of the reactants and the thermodynamic stability of the products, as calculated with molecular mechanics. Key words: D-ribono-1,4-lactone, 2-deoxy-D-ribono-1,4-lactone, acetal, ketal.
- Han, So-Yeop,Joullie, Madeleine M.,Petasis, Nicos A.,Bigorra, Joaquim,Corbera, Jordi,et al.
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p. 349 - 362
(2007/10/02)
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- Stereospecific 1,2-Silyl Shift in a Cationic Rearrangement with Retention of Configuration at the Migration Origin
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Mitsunobu reaction on the hydroxy acids 5 and 10 stereospecifically gave the lactones 7 and 4, respectively, with retention of configuration at C-4.
- Fleming, Ian,Ghosh, Sunil K.
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p. 1777 - 1779
(2007/10/02)
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- Regiocontrol synthesis of β-trimetylsilyloxy carbonyl compounds through an aldolgrignard elaboration sequence
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Reaction of carbonyl compounds with α-lithio- or α-halozinc N-methoxy-N-methylamides, followed by silylation and Grignard addition resulted in a regiocontrolled synthesis of β-trimethylsilyloxy carbonyl compounds.
- Palomo, Caludio,Aizpurua, Jesus M.,Aurrejoetxea, Natalia,Lopez, M. Conception
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p. 2525 - 2528
(2007/10/02)
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