Nucleosides and nucleotides. 186. Synthesis and biological activities of pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety.

Pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety were designed as potential antitumor and/or antiviral agents. Pd (O)-catalyzed reactions of enantiomerically pure (+)-(1R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-1-(ethoxycarbonylo xy)-2- cyclopentene (9) with N3-benzoylthymine and -uracil gave carbocyclic nucleosides 10 and 11. Subsequent Pd (O)-catalyzed reactions of N3-benzoyl-1-[(1R,4S)-4-(ethoxycarbonyloxy)-2-cyclopenten-1- yl]thymine (14) and -uracil (15) with O-benzylhydroxylamine smoothly gave the hydroxyamino-substituted carbocyclic nucleosides 16 and 17. From these nucleosides, the target compounds were prepared after deprotection or further reactions. The 2',3'-didehydro-2',3'-dideoxythymidine (D4T) analogue 20 was the most effective compound, with IC50 values of 27.3 and 34.5 microM against KB and L1210 cells in vitro. Carbocyclic analogues of uridine and cytidine (29 and 32) were less effective than 20 against both cell lines.     

Norbornane as the novel pseudoglycone moiety in nucleosides

Novel nucleoside analogues based on bicyclo[2.2.1]heptene/heptane were prepared by linear synthesis starting from commercially available 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene 1. The crucial step of the synthesis was insertion of the amino group to the position 7 of the substituted bicyclo[2.2.1]heptene with anti-configuration by a Ritter reaction (H₂SO₄, AcOH, CH₃CN). All nucleobases were constructed at this amino function. The prepared family of the target nucleosides was tested for cytostatic and antiviral activity.     

Key side products due to reactivity of dimethylmaleoyl moiety as amine protective group

Dimethylmaleoyl (DMM) moiety has become an important amine protective group in sugar chemistry. We disclose herein that DMM-containing D-glucosamine analogues, because of their electrophilic nature, are prone to reactions with strong nucleophiles, such as hydrazine, resulting in a set of undesired side products that are difficult to detect, yet proved to be problematic for organic synthesis.     

Synthesis and properties of spiro nucleosides containing the barbituric acid moiety

The two chiral spiro nucleosides 4 and 5 containing the barbituric acid moiety were efficiently synthesized from optically pure precursors, and their properties were studied. The carbocyclic nucleoside 5 is considerably more stable against ring opening than the deoxyribosyl derivative 4. Both compounds present enhanced hydrogen bonding capacity with diacetyladenosine.     

赛吲哚霉素糖部分的合成

本文从D-葡萄糖用已知方法经过12步反应得到4-去氧-D-核吡喃已糖(2), 在强酸型离子交换树脂Dowex 50W催化下, 用无水甲醇将其甙化, 生成的甲基甙3和丙酮于无水硫酸酮存在下反应, 钭2,3-二羟基保护得到缩酮4, 采用四氧化钌-过碘酸钠在含水丙酮溶液中氢化4, 得到羧酸5, 5较不稳定, 易发生脱缩酮反应, 用非酸性的1-甲基-3-对甲苯基三氮烯进行酯化, 得到甲酯6, 最后在醋酸水溶液中水解即得目的化合物, 4-去氧-β-D核-吡喃糖甲基甙糖丙基酸甲酯.     

Chemical and structural implications of 1',2'- versus 2',4'- conformational constraints in the sugar moiety of modified thymine nucleosides

In order to understand how the chemical nature of the conformational constraint of the sugar moiety in ON/RNA(DNA) dictates the duplex structure and reactivity, we have determined molecular structures and dynamics of the conformationally constrained 1',2'-azetidine- and 1',2'-oxetane-fused thymidines, as well as their 2',4'-fused thymine (T) counterparts such as LNA-T, 2'-amino LNA-T, ENA-T, and aza-ENA-T by NMR, ab initio (HF/6-31G** and B3LYP/6-31++G**), and molecular dynamics simulations (2 ns in the explicit aqueous medium). It has been found that, depending upon whether the modification leads to a bicyclic 1',2'-fused or a tricyclic 2',4'-fused system, they fall into two distinct categories characterized by their respective internal dynamics of the glycosidic and the backbone torsions as well as by characteristic North-East type sugar conformation (P = 37 degrees +/- 27 degrees , phi(m) = 25 degrees +/- 18 degrees ) of the 1',2'-fused systems, and (ii) pure North type (P = 19 degrees +/- 8 degrees , phi(m) = 48 degrees +/- 4 degrees ) for the 2',4'-fused nucleosides. Each group has different conformational hyperspace accessible, despite the overall similarity of the North-type conformational constraints imposed by the 1',2'- or 2',4'-linked modification. The comparison of pK(a)s of the 1-thyminyl aglycon as well as that of endocyclic sugar-nitrogen obtained by theoretical and experimental measurements showed that the nature of the sugar conformational constraints steer the physicochemical property (pK(a)) of the constituent 1-thyminyl moiety, which in turn can play a part in tuning the strength of hydrogen bonding in the basepairing.     

Mass spectral study of cyclic alkaneboronates of sugar phosphates. Evidence of interaction between the phosphate group and boron under electron-impact conditions

Cyclic butane- and methaneboronic esters of dimethylphosphates of glucose, galactose, mannose, fructose and methyl gluconate have been examined by mass spectrometry. High resolution information and deuterium labeling of all six carbons of glucose, as well as of the methylphosphate groups, permits elucidation of the origin of various ions, which can be grouped according to their probable mechanism of formation. In each case, the intensity of the [M – R]⁺ ion can be rationalized, in stereochemical terms, by the ease with which incipient positive charge on boron can be stabilized by the phosphate group. This interaction also gives rise to rearrangement ions containing a B? O? P linkage. Other effects of structure on fragmentation pattern are discussed. Retention of specific portions of the glucose skeleton in ions with clearly defined label shift behavior, as well as the preservation of intact sugar moieties in intense [M – R]⁺ ions, suggests applications for stable isotope analyses. These are discussed in terms of their advantages over silicon-containing derivatives.     

A toyocamycin analogue with the sugar moiety in a syn conformation

The title compound [systematic name: 4‐amino‐5‐cyano‐1‐(β‐d ‐ribofuranosyl)‐7H‐pyrrolo[2,3‐d]pyrimidine hemihydrate], C₁₂H₁₃N₅O₄·0.5H₂O, is a regioisomer of toyocamycin with the ribofuranosyl residue attached to the pyrimidine moiety of the heterocycle. This analogue exhibits a syn glycosylic bond conformation with a χ torsion angle of 57.51 (17)°. The ribofuranose moiety shows an envelope C2′‐endo (²E) sugar conformation (S‐type), with P = 161.6 (2)° and τ_m = 41.3 (1)°. The conformation at the exocyclic C4′—C5′ bond is +sc (gauche, gauche), with a γ torsion angle of 54.4 (2)°. The crystal packing is stabilized by intermolecular O—H...O, N—H...N and O—H...N hydrogen bonds; water molecules, located on crystallographic twofold axes, participate in interactions. An intramolecular O—H...N hydrogen bond stabilizes the syn conformation of the nucleoside.     

A DFT study of reactions of methyldiazonium ion with DNA/RNA nucleosides: Investigating effect of sugar moiety on methylation pattern of bases

Methyldiazonium ion ( ) is an ultimate carcinogen that can methylate multiple sites in DNA/RNA. In present contribution, density functional theory calculations using the B3LYP and M06‐2X functionals and the 6‐31G(d,p) and aug‐cc‐pVDZ basis sets are carried out to study methylation reactions of at the different nucleophilic sites of DNA/RNA bases and their nucleosides. Total 12 nucleophilic sites, that is, the N2, N3, N7, and O6 sites of guanine; the N1, N3, N6, and N7 sites of adenine; O2 and N3 sites of cytosine and the O2 and O4 sites of thymine and uracil have been considered for study. Thus, a total of 30 reactions have been studied here. The polarizable continuum model is used for solvation calculations. The N7 site of guanine, N7(G), is found to be most reactive in all the reactions studied here, which is in agreement with experiment. However, the calculated reactivity of toward the N7(G) site in aqueous media follows the order: guanine > deoxyguanosine > guanosine. The reactivities of many other sites including the O6(G), O2(C), and N3(A) sites are also modified in going from DNA/RNA bases to their nucleosides and from DNA to RNA nucleosides. Thus, we note that the presence of sugar moiety significantly modifies the methylation pattern of bases caused by . © 2014 Wiley Periodicals, Inc.     

Reductive modification of difluoromethylene moiety in pentafluoropropionyl group

The reductive Mg-promoted defluorinative-silylation of 2,2,3,3,3-pentafluoropropiophenone readily produces the α-trifluoromethyl enol silyl ether, which then react with electrophiles to give a variety of 2-substituted-3,3,3-trifluoropropiophenones in excellent yields. The same protocol is applicable for the preparation of enol silyl ether of 3,3,3-trifluoropropiophenone. Fluoride ion catalyzed 1,2-desilylative-defluorination of 2,3,3,3-tetrafluoro-2-trimethylsilyloxypropiophenone provided 3,3,3-trifluoro-1-phenyl-1,2-propanedione in a good yield.     

Selective phosphitylation of the primary hydroxyl group in unprotected carbohydrates and nucleosides

[reaction: see text] Carbohydrates and nucleosides containing a phosphate at the less-hindered primary hydroxyl group are often prepared using a protection/deprotection strategy. Herein we report that the phosphoramidite method can be used to selectively incorporate phosphorus at the primary hydroxyl group of O-unprotected carbohydrates and nucleosides; in situ oxidation of the resulting phosphite triester yields the phosphate triester.     

Spin trapping in the interaction between acetylenic hydrocarbons and group VIB metal carbonyls

1-Heptyne and 2-heptyne were reacted with Mo(CO)₆ (M=Cr, Mo, W) under different conditions. All samples exhibit ESR signals only in the presence of spin traps. Both carbon-centered and metal-centered radicals have been observed. The radical intermediates were identified by isotropic g-values and splitting constants for nitrone spin adducts obtained from the reaction systems under various conditions.     

Design and divergent synthesis of aza nucleosides from a chiral imino sugar

Several novel nucleoside analogues as potential inhibitors of glycosidases and purine nucleoside phosphorylase (PNP) have been synthesized via selective coupling of an appropriate nucleobase at different positions of an orthogonally protected imino sugar as a common precursor. This synthetic strategy offers a straightforward protocol for the assembly of imino sugar containing nucleosides, establishing a new repertoire of molecules as potential therapeutics.     

Direct interaction between an allosteric agonist pepducin and the chemokine receptor CXCR4

Cell surface heptahelical G protein-coupled receptors (GPCRs) mediate critical cellular signaling pathways and are important pharmaceutical drug targets. (1) In addition to traditional small-molecule approaches, lipopeptide-based GPCR-derived pepducins have emerged as a new class of pharmaceutical agents. (2, 3) To better understand how pepducins interact with targeted receptors, we developed a cell-based photo-cross-linking approach to study the interaction between the pepducin agonist ATI-2341 and its target receptor, chemokine C-X-C-type receptor 4 (CXCR4). A pepducin analogue, ATI-2766, formed a specific UV-light-dependent cross-link to CXCR4 and to mutants with truncations of the N-terminus, the known chemokine docking site. These results demonstrate that CXCR4 is the direct binding target of ATI-2341 and suggest a new mechanism for allosteric modulation of GPCR activity. Adaptation and application of our findings should prove useful in further understanding pepducin modulation of GPCRs as well as enable new experimental approaches to better understand GPCR signal transduction.