Correlation of the C-1′ chemical shifts with the vicinal spin-spin coupling constants of the H-1′ and H-2′ protons in nucleosides. II. 2′-, 3′-, and 5′-O-substituted nucleosides

The existence of a correlation has been established for pyrimidine but not for purine, nucleosides. It is suggested that the change in the chemical shift of the anomeric carbon is a consequence of 1,2-eclipsing interaction between O-2′ and N-1′ in the S type of conformation of the ribose ring. Possible reason for the absence of a correlation in the case of purine nucleosides are discussed. It is shown that the chemical shift of the anomeric carbon can be used in the conformational analysis of the ribose rings of pyrimidine nucleosides.     

Use of allyl, 2-tetrahydrofuryl, and 2-tetrahydropyranyl ethers as useful C3-, C4-, and C5-carbon sources: palladium-catalyzed allylation of aldehydes

Palladium-diethylzinc or palladium-triethylborane catalytically promotes self-allylation of 2-(allyloxy)tetrahydrofurans, 2-(allyloxy)tetrahydropyrans, and their hydroxy derivatives on the rings (ribose, glucose, mannose, deoxyribose, deoxyglucose). All the reactions proceed at room temperature and provide polyhydroxyl products, sharing a structural motif of a homoallyl alcohol, in good to excellent yields with high levels of stereoselectivity. Useful C3-unit elongation, which makes the best use of an allyl ether as a protecting group and a nucleophilic allylation agent, is demonstrated. Mechanisms for the umpolung reaction (of an allyl ether into an allylic anion) and stereoselectivity associated with allylation of aldehydes are discussed.     

Synthesis of [5'-13C]ribonucleosides and 2'-deoxy[5'-13C]ribonucleosides

The present efficient synthesis of [5'-13C]ribonucleosides and 2'-deoxy[5'-13C]ribonucleosides is characterized by the synthesis of the D-[5-13C]ribose derivative as an intermediate via the Wittig reaction of 4-aldehydo-D-erythrose dialkyl acetals with Ph3P13CH3I-BuLi to introduce the 13C label at the 5-position of a pentose. This was followed by the highly diastereoselective osmium dihydroxylation for the preparation of 2,3-di-O-benzyl-D-[5-13C]ribose dialkyl acetal and the cyclization from D-[5-13C]ribose dialkyl acetal derivatives to the alkyl D-[5-13C]ribofuranoside derivative by the use of LiBF(4). The obtained D-[5-13C]ribose derivative was converted into [5'-13C]ribonucleosides and subsequently into the corresponding 2'-deoxynucleosides.     

Chemoenzymatic synthesis of 7-deaza cyclic adenosine 5'-diphosphate ribose analogues, membrane-permeant modulators of intracellular calcium release

An optimized synthetic route to 7-deaza-8-bromo-cyclic adenosine 5'-diphosphate ribose (7-deaza-8-bromo-cADPR 3), an established cell-permeant, hydrolysis-resistant cyclic adenosine 5'-diphosphate ribose (cADPR) antagonist, is presented. Using NMR analysis, we found that 3 adopted a C-2' endo conformation in the N9-linked ribose and a syn conformation about the N9-glycosyl linkage, which are similar to that of cADPR. The synthetic route was also employed to produce 7-deaza-2'-deoxy-cADPR 4, a potential cell-permeant cADPR analogue. 3 and 4 were more stable to chemical hydrolysis, consistent with the observation that 7-deaza-cADPR analogues are more stable than their parent adenosine derivatives. 3 was also found to be stable to enzyme-mediated hydrolysis using CD38 ectoenzyme.     

Complexes of copper(II) with adenosine or guanosine nucleosides, nucleotides 5'-monophosphate, 2'-deoxynucleosides or 2'-deoxynucleotides 5'-monophosphate in aqueous solution

In this paper copper(II) complex formation in aqueous solution with a series of nucleosides (adenosine or guanosine) or nucleotides 5'-monophosphate is studied by means of potentiometry, visible spectrophotometry and ultraviolet circular dichroism. A chemical model has been formulated for each binary system (at T= 25 degrees C and I = 0.1 M), with particular attention to the interaction in the basic field. A spectrum (both visible absorption and ultraviolet circular dichroism) for each complex with a significant percentage of formation (in the adopted experimental conditions) has been calculated, allowing structural details to be hypothesised. The interaction with deprotonated alcoholic group(s) of the ribose moiety has been found to be fundamental in determining the co-ordination chemistry of each ligand considered while cases of co-operation between the purine and ribose donor(s) were also considered. Confirmations were also obtained by an investigation on the corresponding 2'-deoxy compounds as ligands.     

An efficient procedure for the preparation of (1S,3R)- and (1S,3S)-1-amino-3-(hydroxymethyl)cyclopentanes

Enantiomerically pure (1S,3S)- and (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentanes have been efficiently synthesized from L-aspartic acid. The title compounds are isosteres of ribose and may be used to construct nucleoside analogs with important antiviral and antineoplastic activities as demonstrated by a concise total synthesis of (+)-4'-deoxycarbapentostatin nucleoside.     

Total synthesis of a cyclic adenosine 5'-diphosphate ribose receptor agonist

Stable cyclic adenosine 5'-diphosphate ribose (cADPR) analogues are chemical biology tools that can probe the Ca(2+) release mechanism and structure-activity relationships of this emerging potent second messenger. However, analogues with an intact "northern" ribose have been inaccessible due to the difficulty of generating the sensitive N1-ribosyl link. We report the first total synthesis of the membrane permeant, hydrolytically stable, cADPR receptor agonist 8-Br-N1-cIDPR via regio- and stereoselective N1-ribosylation of protected 8-bromoinosine.     

Conformational properties of the 2′- and 3′-hydroxy groups of 5′-O-trityluridine

The results of a study of the temperature dependence of the SSCCs of the hydroxyl protons in the PMR spectra of 5′-O-trityluridine indicate the existence of an intramolecular bond between the 2-keto oxygen of the base and the 2′-hydroxyl in deuterochloroform. Under these conditions, stabilization of the 3′-endo (N) conformation of the ribose ring is observed. The existence of the influence of the temperature on the population of the 3′-hydroxyl rotamers shows the formation of a hydrogen bond between OH-3′ and O-2′. In polar solvents free rotation of the hydroxy groups is observed.     

Cyclic Adenosine 5′‐Diphosphoribose (cADPR) Mimics Used as Molecular Probes in Cell Signaling

Cyclic adenosine 5′‐diphosphate ribose (cADPR) is a second messenger in the Ca²⁺ signaling pathway. To elucidate its molecular mechanism in calcium release, a series of cADPR analogues with modification on ribose, nucleobase, and pyrophosphate have been investigated. Among them, the analogue with the modification of the northern ribose by ether linkage substitution (cIDPRE) exhibits membrane‐permeate Ca²⁺ agonistic activity in intact HeLa cells, human T cells, mouse cardiac myocytes and neurosecretory PC12 cell lines; thus, cIDPRE and coumarin‐caged cIDPRE are valuable probes to investigate the cADPR‐mediated Ca²⁺ signal pathway.     

Comprehensive Comparisons between 1-Phenyl-3-methyl-5-pyrazolones, 1-(4-Methoxyphenyl)-3-methyl-5-pyrazolones and 1-(2-Naphthyl)-3-methyl-5-pyrazolones as Labeling Reagents Used in LC-DAD-ESI-MS-MS Analysis of Neutral Aldoses and Uronic Acids

Comprehensive comparisons between three 1-aryl-3-methyl-5-pyrazolone (AMP) labeling reagents were carried out for the analysis of reductive monosaccharides using reversed phase high performance liquid chromatography diode array detection coupled to electrospray ionization mass spectrometry. AMP derivatives included 1-phenyl-3-methyl-5-pyrazolone (PMP), 1-(4-methoxyphenyl)-3-methyl-5-pyrazolone (PMPMP) and 1-(2-naphthyl)-3-methyl-5-pyrazolone (NMP). The separation of AMP-monosaccharides was found to be pH-dependent under reversed phase conditions and acceptable separations were obtained at pH < 4.5. The elution orders of AMP-aldoses were rationalized by geometric factors involved in the presence of hydroxyl groups at C2 and C3 positions of the saccharide moiety. When PMP or PMPMP were used as labeling agents Glucose and galactose were completely separated, while arabinose and xylose were observed to co-elute. The use of NMP revealed that arabinose and xylose could be separated while glucose and galactose were co-eluted. MS-MS data of AMP-monosaccharides gave characteristic fragment ions resulting from cleavage between the C2–C3 bond (m/z 373 for PMP derivatives, m/z 433 for PMPMP derivatives, and m/z 473 for NMP derivatives). Bond breakage between C1–C2 (m/z 359 for PMP derivatives, m/z 419 for PMPMP derivatives, and m/z 459 for NMP derivatives) of the saccharide moiety was also found to be characteristic for AMP-saccharides. Application to the analysis of hydrolyzed rape pollen polysaccharides revealed the presence of four unexpected monosaccharides, namely ribose, erythrose, threose and glyceraldehyde.     

Theoretical study on the factors controlling the stability of the borate complexes of ribose, arabinose, lyxose, and xylose

Recent experimental studies suggest that complexation with borate minerals stabilizes ribose, and that the borate complex of ribose is more stable than those of related aldopentoses, that is, arabinose, lyxose, and xylose. These findings have revived the debate on the plausibility of the RNA-world theory, because they provide an explanation for the stabilization and selection of ribose in prebiotic conditions. In this paper we unravel the factors that make the ribose-borate complex the most stable one. For this purpose, we have investigated the structure and stability of the ribose-, arabinose-, lyxose-, and xylose-borate complexes using density functional theory and a continuum solvent approach. The computed results reveal that in the aldopentose-borate complexes, the electrostatic field of the borate is strong enough to change the orientation of the nearby hydroxyl groups compared to noncomplexed aldopentoses. In addition, we show that the distinct stability of the ribose-borate 2:1 complex can be attributed to 1) a strong hydrogen bond between the ribose 3-OH and one of the negatively charged borate oxygen atoms, and 2) a favorable contact between the aqueous medium and the 5-CH(2)OH group due to the space separation between the 5-CH(2)OH group and the borate anion.     

Rapid synthetic route toward structurally modified derivatives of cyclic adenosine 5'-diphosphate ribose

A concise synthesis of five new analogues of the second messenger cADPR (cyclic adenosine 5'-diphosphate ribose) is presented. The synthetic plan centered around the key derivative 8-Br-N1-cIDPR (cyclic 8-Br-inosine 5'-diphosphate ribose, 2), which was prepared in only three steps from IMP (inosine 5'-monophosphate) via an unusual enzymatic cyclization reaction. The enhanced stability of 2 allowed for the direct modification of this cyclic dinucleotide at the 8 position, providing the unsubstituted parent N1-cIDPR (4) as well as the 8-phenyl (5), 8-azido (6), and 8-amino (7) N1-cIDPR analogues. In Jurkat T-lymphocytes, N1-cIDPR 4 induced Ca2+ release with an almost identical profile as the natural agonist cADPR, illustrating the value of this approach.     

Regioselective synthesis of beta-N1- and beta-N3-alloxazine nucleosides

[structures: see text] A regio- and stereoselective glycosylation of ribose tetraester with persilylated alloxazine to give either beta-N1 or beta-N3 nucleosides is described. The N3 product is potentially of interest as a fluorescent nucleoside and is predicted to have the hydrogen-bonding characteristics of thymidine.     

Negative ion FAB mass spectroscopy of some ribose alkylated 5'-UMP derivatives

Characteristic fragment ions obtained in Fast atom bombardment (FAB) mass spectroscopy of ribose alkylated Uridine 5'-monophosphate (5'-UMP) derivatives in negative ion mode are described. All the compounds examined exhibited either [M]- or quasimolecular ion [M - H]- the fragmentations can be used to characterize these nucleotides.     

Synthesis of cyclic adenosine 5'-diphosphate ribose analogues: a C2'endo/syn "southern" ribose conformation underlies activity at the sea urchin cADPR receptor

Novel 8-substituted base and sugar-modified analogues of the Ca(2+) mobilizing second messenger cyclic adenosine 5'-diphosphate ribose (cADPR) were synthesized using a chemoenzymatic approach and evaluated for activity in sea urchin egg homogenate (SUH) and in Jurkat T-lymphocytes; conformational analysis investigated by (1)H NMR spectroscopy revealed that a C2'endo/syn conformation of the "southern" ribose is crucial for agonist or antagonist activity at the SUH-, but not at the T cell-cADPR receptor.     

Regio- and stereoselective glycosylation: synthesis of 5-haloimidazole alpha-ribonucleosides

We describe the synthesis of novel 5-haloimidazole ribonucleosides as precursors of modified cobalamins. A regio- and stereoselective glycosylation of protected ribose with silylated 4(5)-haloimidazoles produces 5-haloimidazole ribonucleosides predominantly in the alpha-configuration (60-75%) without any 4-substituted imidazole ribonucleoside. The structure of the 5-fluoroimidazole ribonucleoside was confirmed by X-ray crystallography and 2D NMR spectroscopy.     

Synthetic approaches to imino sugar (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-3,4-diol from naturally occurring sugar and amino acid

Imino sugar compound 3 was prepared by two alternative routes starting from ribose and d-serine. From d-serine (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methylpyrrolidin-2-one was prepared in five steps in 50% overall yield, which was further converted into (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-3,4-diol in three steps in 23% overall yield.     

Towards the improvement of the synthesis of novel 4(5)-aryl-5(4)-heteroaryl-2-thio-substituted imidazoles and their p38 MAP kinase inhibitory activity

A series of 2-alkylsulfanyl-4-(4-fluorophenyl)-5-(2-aminopyridin-4-yl)-substituted imidazoles was prepared and interaction possibilities of the 2-thioether moiety with phosphate/ribose binding pockets of p38 MAP kinase were investigated. Introduction of the alkyl/benzyl amino function at the pyridine moiety was carried out via nucleophilic substitution or via palladium catalyzed aryl-C-N-bond formation.     

Unusual entry to the novel 8-halo-N1-ribosyl hypoxanthine system by degradation of a cyclic adenosine-5'-diphosphate ribose analogue

Cyclic 8-bromo-inosine-5'-diphosphate ribose (8-Br-N1-cIDPR) was cleanly degraded at acidic pH by N9 ribosyl scission and subsequent pyrophosphate cleavage to give 8-bromo-N1-ribosyl hypoxanthine 5'-monophosphate (8-Br-N1-IMP), a novel class of mononucleotide, as the sole product.     

A general,stereocontrolled entry to pyrimidine homo-C-nucleosides

A simple synthesis of nucleoside analogues with a methylene group between the ribose and 5-position of pyrimidine appendages is outlined.