Large Scale Synthesis of the Cap Part in Messenger RNA Using a New Type of Bifunctional Phosphorylating Reagent

Abstract

Bifunctional phosphorylating reagents 1 and 2 were employed for the synthesis of the cap part, m⁷G⁷ pppG, from guanosine 5′-phosphates on a large scale without any protecting groups.     

Synthetic Approaches to Rare 2-Substituted Purine Nucleosides

Abstract

The syntheses of several novel functional1zed 2-subst1tuted purine nucleosides are described. Key reactions In these transformations Include photolnduced reductive dehalogenatlon, radical deamlnatlon-halogenatlon, and functional1zed carbon-carbon bond formation Involving palladium catalysis. An Interesting ring opening reaction of 2-iodopur1ne nucleoside to an Imidazole derivative under S_RN conditions is mentioned. High-f1eld ¹³C NMR data suggest that the 2-subst1tuted purine nucleosides prefer the anti conformation 1n solution. Biological evaluation of these compounds is currently being carried out.     

Syntheses,Activites Biologiques et Etude Conformationnelle D'Alcynyl-5 Desoxy-2′ Uridines

Abstract

5-Alkynyl 2′-deoxyuridines were prepared in low to modest yields by the palladium and nickel-catalyzed reaction of alkynylzinc reagents with 0–3′, 5′-bis (trimethylsilyl) deoxyuridine in THF. ¹H-NMR and ¹³C-NMR studies showed that, in DMSO-d⁶, these synthesized nucleosides have the anti conformation as for the glycosidic bond and that the S conformation of the 2-deoxyribose ring is preponderant. 5-(5-Chloro-1-pentynyl) dUrd (6c) exhibited a potent antiviral activity, reminiscent of that reported before for 5-ethynyl-dUrd and 5-propynyl-dUrd. However, none of these 5-ethynyl-dUrd analogues proved selective in its antiviral action.     

The Synthesis and Preliminary Biological Evaluations of Selected Analogues of the Potent Broad-Spectrum Antiviral Agent Ganciclovir 1′,3′-Cyclic Monophosphate1 (2′-Nor-cGMP)

Abstract

The syntheses and antiviral activity of a series of analogues of the potent antiherpetic 2′-nor-cGMP are described. These derivatives contain systematic changes in either the heterocycle, the acyclic moiety, or the phosphate ring.     

Studies on Nucleoside H-Phosphonothioates as Synthons in the Synthesis of Oligonucleotide Analogues

Abstract

Recently, we have reported that H-phosphonothioate diesters¹ are versatile synthetic intermediates for the preparation of phosphorothioates, phosphorodithioates, or other phosphodiester analogues. The most suitable coupling agents to produce Hphosphonothioate diesters were found to be various chlorophosphates¹ [e.g., 2-chloro-5,5-dimethyl-2-oxo-2λ⁵-1,3,2-dioxaphosphinane (NEP), diphenyl phosphorochloridate]. These reagents secure the required chemoselectivity during the condensation and are unreactive towards the P-H function in H-phosphonothioate diesters^1,2.     

Synthesis of Two 2′-Deoxyuridine Analogs Substituted in Position 5 with 2-Atom Tethered Nitroxide Radicals

Abstract

The synthesis of two novel spin labeled 2′-deoxyuridine analogs is described. The nucleic acid building block is substituted in position 5 with a short methylamino tether, which bears either a six- or five-membered nitroxide ring.     

The mechanisms for N-heterocyclic olefin-catalyzed formation of cyclic carbonate from CO<Subscript>2</Subscript> and propargylic alcohols

The mechanistic details of N-heterocyclic olefin-catalyzed formation of cyclic carbonate from CO₂ and propargylic alcohols were investigated by DFT calculations. Six mechanisms, four for the formation of five-membered cyclic carbonate (M-A, M-B, M-B’ and M-C), and two for six-membered cyclic carbonate (M-D and M-E), were fully investigated. The energy profiles in dichloromethane showed that M-B is the predominant reaction with the lowest barrier of 31.99 kcal mol^?1, while M-C and M-D may be kinetically competitive to M-B. The very high activation energy of 45.37 kcal mol^-1, 57.07 kcal mol^-1 and 59.61 kcal mol^?1 for M-A, M-B’ and M-E, respectively, suggest that they are of lesser importance in the overall mechanism.

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Graphical abstract Formations of five-membered ring product and six-membered ring product are kinetically competitive, but five-membered ring product is thermodynamically more preferable.

     

Trichloro-tert.-butyl-cyclic-enediol-phosphate (TCB-CEP), Proposed Reagent for the Syntheses of Oligonucleotides Using the Triester Approach

Abstract

Protected nucleosides, phosphorylated using 4, 5-dimethyl-2-oxo-2-trichloro-tert.-butyl-l, 3, ^λ5-dioxaphos-pholene, can be cleaved to yield either 5′- or 3′-building blocks for triester syntheses.     

A systematic study of the stabilities of cyclic boryl anions

In this study, we perform several DFT functionals and post-SCF methods (MP2 and CCSD(T)) to investigate the stability of a series of virtual cyclic boryl anions. This investigation stems from two aspects: (1) the energetic difference between S₀ and T₁ states and (2) the electron affinity of the cyclic boryl anions. The results are systematically discussed in terms of substitution effect, influence of the steric effect, number of nitrogen atoms, the ring size and solvation inclusion. Moreover, the effect of the counter cation Li⁺ on the singlet-triplet splitting is also investigated. Among various boryl anions studied, the results predict bulky-group substituted 5i and 8, shown in Schemes 3 and 4, respectively, to be stable anions in gas phase as well as in organic solvents. Since boryl anions may be exploited to synthesize new boron-containing compounds as well as to provide synthetic routes different from traditional protocols, the predicted thermodynamically stable 5i and 8 are then of both synthetic interest and challenging for future applications of cyclic boryl anions.     

Theoretical study of [ XN5 ]− (X=O, S, Se, Te) systems

A series of [XN₅]⁻ (X=O, S, Se, Te) compounds has been examined with ab initio and Density Functional Theory (DFT) methods. The five-membered nitrogen ring series of structures are global minima and may exist or be characterized due to their significant dissociation barriers (29.7–32.7 kcal mol⁻¹). Nucleus-independent chemical shifts (NICS) criteria and the presence of (4n+2) π-electrons confirmed that the five-membered nitrogen ring in their structures exhibits characteristics of aromaticity. Thus, the strong stability of the five-membered nitrogen ring structures may be attributed partially to their aromaticity.      

Reusable Solid-Phase Supports for Oligonucleotide Synthesis Using Hydroquinone-O,O'-diacetic Acid (“Q-Linker”)

Abstract

Reusable solid-phase supports for large scale oligonucleotide synthesis have been prepared by converting amino derivatized supports into hydroxyl supports. Rapid nucleo side attachment, via a Q-linker arm, was automatically performed on the DNA synthesizer using HBTU and DMAP as the coupling reagents. All steps were suitable for automation and ～ 1.5 h was required to prepare the supports for reuse. Up to twelve consecutive syntheses of a 20-mer phosphorothioate were performed on a synthesis column.     

Correlated Variations of Bond Lengths in Pseudorotating Furanose Rings

Abstract

Correlated variations of bond lengths in pseudorotating furanose rings are investigated by a theoretical method. At first, matrix equations are proposed to determine the spatial coordinates of the ring atoms from the bond lengths, the bond angles, and the pseudorotation parameters. Secondly, a necessary functional form of the variations of the bond lengths of five-membered rings is derived from a consideration of symmetry. Finally, demonstrations are performed on a furanose ring whose bond angle variations have been precisely determined by experimental analyses. The resulting bond length variations are:

δR_i = β_iCos(8/5π · (i-2)+2P)

where δR_i is the variation of the bond length between atoms i and i+1, P is the pseudorotation phase, and β_iis a negative constant about ?0.01 Å. These bond length variations are balanced on the apparent strains of the bond lengths and the bond angles.     

Interaction of Cyclic AMP Derivatives with the Angiotensin II Receptor

Abstract

The effect of cyclic AMP and of its derivatives was studied on ¹²⁵I-angiotensin II and ¹²⁵I- (Sar¹, Ala⁸) -angiotensin II binding to rat adrenal membrane receptors. Dibutyryl cyclic AMP, 8-bro-mo-cyclic AMP and cyclic AMP inhibited both agonist and antagonist binding in a specific and dose-dependent way, with K₁ of 1.3 mM, 6.8 mM and about 30 mM, respectively. Scatchard analysis of binding data indicated that the nucleotides interacted directly with the membrane receptor for angiotensin II. These results suggest that cyclic AMP may act extracellularly and affect receptor-mediated events.     

Synthesis and conformational analysis of 1,2-cis fused bicyclic α-d-galactofuranosyl thiocarbamate from per-O-tert-butyldimethylsilyl-β-d-galactofuranosyl isothiocyanate

Per-O-tert-butyldimethylsilyl-α,β-d-galactofuranosyl isothiocyanate (4) was synthesized by the reaction of per-O-TBS-β-d-galactofuranose (1) with KSCN, promoted by TMSI. Upon O-desilylation (1,2-dideoxy-α-d-galactofuranoso)[1,2d]-1,3-oxazolidine-2-thione (6), the cis-fused bicyclic thiocarbamate was obtained as the only product. Conformational analysis, aided by molecular modelling, showed two stable twist forms (³T₄ and ⁴T_O) for the five-membered sugar ring in 6. In aqueous solution, the equilibrium favours the first conformation (3:1 ratio). On the other hand, this ratio decreases for less polar solvents.     

RNA Modified Uridines. V. An Improved Synthesis of 3-[3-(S)-Amino-3-carboxypropyl]uridine (acp3U) and Its 5′-Phosphate

Abstract

The condensation of 2′,3′-0-isopropylideneuridine sodium salt 3 with benzyl 2-(S)-benzyloxycarbonylamino-4-iodobutyrate 2a derived from L-homoserine, followed by the deprotection of 4a in mild conditions gives the title nucleoside 1a in 68% yield. The syntheses of acp³U 3R-epimer 1b and of acp³U 5′-phosphate 6 are also described.     

Conformational Studies of Nucleic Acids I. A Rapid and Direct Method for Generating Furanose Coordinates from the Pseudorotation Angle

Abstract

The greatest difficulty in modeling a nucleic acid is generating the coordinates of its furanoses. This difficulty arises from constraints imposed by the closed ring geometries of these sugars. We have developed a new method for modeling these furanose rings. Using this method, the coordinates of a sugar can be obtained quickly and unambiguously for any point on the pseudorotational pathway from one parameter: the phase angle of pseudorotation P. The significant difference between this and previous sugar modeling schemes is that here the endocyclic bond lengths of the five-membered sugar ring are allowed to vary a small amount according to simple, explicit, and experimentally reasonable analytic functions of P. The coefficients of these functions follow from the empirical behavior of the endocyclic bond angles and from geometrical constraints due to ring closure. The ability to model the sugars directly from one parameter greatly facilitates carrying out the global conformational studies on nucleic acid constituents which will be attempted in subsequent papers of this series.     

Crystal and Molecular Structure of (+)-Carba-Thymidine,C11 H10 N2 O6

Abstract

The molecular structure of (+)-carba-thymidine possessing notable anti-HSV activity has been determined by single crystal X-ray diffraction. It crystallizes in the monoclinic space group P2 with unit cell dimensions a = 4.810(2), b = 11.560(1)¹, c = 10.014(1) A, β = 92.34(2)°, Z = 2. The structure was solved by direct methods and refined by least squares to a final R = 0.038 for 1027 reflections (I < 36(I)). The torsion angle x around the glycosidic N1-C1′ bond agrees with that of thymidine (37.5°vs 39.1°) whereas the C3′-exo pucker of the five-membered ring is shifted to an even less common C1′-eao form.     

Base-Labile Group Protected Biotinphosphoramidite Reagents for Solid Phase Biotinylation of Oligonucleotides

Abstract

A general and rapid method is described for the synthesis of N¹ -base labile group protected biotinphosphoramidite reagents, useful for the synthesis of biotinylated oligonucleotides in automated DNA synthesizer.     

Glycosylation of Mono- and Bicyclic Dicarbonic Acid Imides

Abstract

Glycosylation of some mono- and bicyclic dicarbonic acid imides was performed via the Friedel-Crafts-catalyzed silyl Hilbert-Johnson reaction. The occurrence of β-N-ribosylation was established by ¹H and ¹³C NMR spectroscopy. The electron distributions in the lactam region of the N-silylated cyclic imides strongly influence the glycosylation. The N-glycosylated cyclic imides are potential agents for glycoalkylation of lysine residues in proteins.