Synthesis of 3′-4′-α-Propylene-2′-3′-dideoxynucleosides

Abstract

In order to obtain a high degree of rigidity within the sugar moiety of nucleosides, some bicyclic pyrimidine nucleoside analogues where synthesized starting from cyclopentanone. The C-4′-substituent is fused to the C-3′-position via a propylene to give a [3.3.0]-bicyclic ring system.     

Synthesis of 2-(3′-Azido- and 3′-Amino-3′-deoxy-β-D-ribofuranosyl)thiazole-4-carboxamide

Abstract

In view of biological activities of tiazofurin and azido or aminosugar nucleosides, novel azido- and amino-substituted tiazofurin derivatives (1 and 2) were efficiently synthesized starting from 1,2;5,6-di-O-isopropylidene-D-glucose.     

3′-Deoxy-3′-Hydroxyamino-β-D-Xylofuranosyluracil and Derivatives Thereof

Abstract

The title compound was prepared by reduction of the oxime of the 3′-ketouridine. Condensation with aldehydes gave a series of nitrones whose reduction afforded “second generation” hydroxylamines, some of which showing antiviral activity. The nitroxide free radicals formed upon oxidation of hydroxylamines gave good e.s.r. spectra useful for configurational and conformational assignments.     

3′-3′,3′-5′ and 5′-5′ TpT-Amides: Synthesis,Characterization and Alkaline Hydrolysis

Abstract

A simple procedure is described for the preparation of the title compounds 1, 8 and 9. 3′-3′ or 3′-5′ or 5′-5′ TpT was reacted with a twofold molar excess of TPS in anhydrous DMF, at room temperature, for 5 min, followed by a 1 min in situ treatment of the reaction mixture with excess 7.0 N NH₄OH, at 0°C. The alkaline hydrolysis of 1, 8 and 9 proceeds without the assistance of 3′- and 5′-hydroxyl groups resulting in equimolar mixtures of thymidine (4) and thymidine 3′-phosphoramidate (6) (for the 3′-3′ isomer) or thymidine 5′-phosphoramidate (7) (for the 5′-5′ isomer) or 6 and 7 in equal quantities (for the 3′-5′ isomer).     

6-chloro-3-β-d-erythrofuranosyl-l-phenyl- and -l-p-tolylpyrazolo-[3,4-b]quinoxaline

The C-nucleoside analogs 6-chloro-3-β-d-erythrofuranosyl-l-phenylpyrazolo-[3,4-b]quinoxaline (5) and 3-β-d-erythrofuranosy]-l-p-tolylpyrazolo[3,4-b]quinoxaline (10) were prepared by dehydration of the polyhydroxyalkyl chain of 6(7)-chlorolo-phenyl-3-(d-arabino-tetritol-l-yl)-pyrazolo(3,4-b]quinoxaline and 3-(d-arbino-tetritol-l-yl)-l-p-tolylpyrazolo[3,4-b]quinoxaline, respectively. The structure and anomeric configuration of 5 and 10 were determined by high-resolution, n.m.r. spectroscopy. The mass spectra and biological activities of some of these compounds are discussed.     

Chemistry and Anti-HIV Activity of 2′-β-Fluoro-2′,3′-dideoxyguanosine

Abstract

The 2′-β-fluoro analogue of 2′,3′-dideoxyguanosine has been prepared by two synthetic routes. This compound and two analogues have anti-HIV activity in at least two of three host cell systems used (ATH8, CEM, PBL). These compounds, as well as their ddGuo parents, have been characterized with regard to their acid-stabilities, octanol-water partition coefficients, and enzyme substrate properties for adenosine deaminase and purine nucleoside phosphorylase. F-ddGuo analogues are less potent but more stable than their non-fluorinated parent compounds.     

Synthesis of the 2′-,3′-Didehydro-2′-,3′-dideoxy and 2′-,3′-Dideoxy Derivatives of 6-Azauridine and a New Route to 2′-,3′-Didehydro-2′-,3′-dideoxy-5-chlorouridine

Abstract

The 5′-O-(4,4′-dimethoxytrityl) and 5′-O-(tert-butyldimethylsilyl) derivatives of 2′-,3′-O-thiocarbonyl-6-azauridine and 2′,3′-O-thiocarbonyl-5-chlorouridine were synthesized from the parent nucleosides by reaction with 4, 4′-dimethoxytrityl chloride and tert-butyldimethylsilyl chloride, respectively, followed by treatment with 1,1′-thiocarbonyldiimidazole. Introduction of a 2′-,3′-double bond into the sugar ring by reaction of the 5′-protected 2′-,3′-O-thionocarbonates with 1, 3-dimethyl-2-phenyl-1, 3, 2-diazaphospholidiine was unsuccessful, but could be accomplished satisfactorily with trimethyl phosphite. Reactions were generally more successful with the 5′-silylated than with the 5′-tritylated nucleosides. Formation of 2′-,3′-O-thiocarbonyl derivatives proceeded in higher yield with 5′-protected 6-azauridines than with the corresponding 5-chlorouridines because of the propensity of the latter to form 2,2′-anhydro derivatives. In the reaction of 5′-O-(tert-butyldimethylsilyl)-2′-,3′-O-thiocarbonyl-6-azauridine with trimethyl phosphite, introduction of the double bond was accompanied by N³-methylation. However this side reaction was not a problem with 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-O-thioarbonyl-5-chlorouridine. Treatment of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-6-azauridine with tetrabutylammonium fluoride followed by hydrogenation afforded 2′-,3′-dideoxy-6-azauridine. Deprotection of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-5-chlorouridine yielded 2′-,3′-didehydro-2′-,3′-dide-oxy-5-chlorouridine.     

Synthesis of 2,2′-Anhydro-1 - (3′ -deoxy -3′ -iodo-β-D-arabino-furanosyl) thymine and Its Derivatives as Versatile Synthetic Intermediates

Abstract

2,2′ -Anhydro-1- (3′ -deoxy-3′ -iodo-5′ -O-trityl-B-D-arabinofuranosyl)-thymine (2) was synthesized from 2′,3′ -didehydro-3′-deoxythymidine (DHT) (1). Compound 2 was readily converted into 2′,3′-anhydro-lyxofuranosyl derivatives 4-6. Reaction of 4a with some nucleophiles (N₃ -, OMe-, Cl-) gave the corresponding 3′-substituted arabinonucleosides (7b,d,f) together with the minor xylosyl isomers (8a,c). Compounds 7b,d,f and 8a were deprotected to 7c,e,g and 8b, respectively.     

Synthesis and Biological Evaluation of (3′S)-3′-Deoxy-3′-Fluoro-3′-C-Ethynylcytidine

The novel pyrimidine nucleoside, (3 ′S)-3 ′-deoxy-3 ′-fluoro-3 ′-C-ethynylcytidine (1) was synthesized from cytidine in seven steps. The key step in the synthesis was the introduction of the tertiary fluorine at the 3 ′-position. Compound 1 was evaluated in vitro against several RNA viruses.     

SYNTHESIS OF SOME 2′-FLUORO-2′-DEOXY-3′-C-ETHYNYL AND 3′-C-VINYL-β-D-LYXOFURANOSYL NUCLEOSIDES

1-(2-Fluoro-2-deoxy-β-D-arabinofuranosyl)uracil (5) and 1-(2-fluoro-2-deoxy-β-D-arabinofuranosyl)cytosine (6) were synthesized as reported earlier. Both of these compounds were converted into 2′-fluoro-2′-deoxy-3′-C-ethynyl and 3′-C-vinyl-β-D-lyxofuranosyl nucleosides (16–19) by a multistep sequence. All these new nucleosides were evaluated against seven human tumor cell lines in vitro.     

Efficient chemoselective synthesis of 3,4′-dihydroxypropiophenone 3-O-β-D-glucoside by thermophilic β-glycosidase from Sulfolobus solfataricus

Summary A comparison of different systems for the -glycosidase-atalyzed synthesis of 3,4-dihydroxypropiophenone 3-O--D-glucoside is reported including various enzymatic sources and different reaction conditions. The best yield was obtained using thermophilic -glycosidase from Sulfolobus solfataricus.     

Beyond paraquats: Dialkyl 3,3′- and 3,4′-bipyridinium amphiphiles as antibacterial agents

Dialkyl 4,4′-bipyridinium compounds, known as ‘paraquats’ (PQs), have a long history of use as herbicides, as redox indicators, and more recently as potent antibacterial agents. However, due to their ability to form reactive oxygen species (ROS) in vivo, PQs are also known to be toxic. We proposed that altering the electrochemical properties of PQ, specifically by preparing isomeric bipyridinium structures with 3,3′- and 3,4′-substitution of the nitrogen heteroatoms on the biaryl core, would maintain antibacterial activity, yet decrease toxicity. We have thus prepared a series of 17 amphiphiles, dubbed ‘metaquat’ (MQ) and ‘parametaquat’ (PMQ), respectively, and investigated their antibacterial and electrochemical properties. Optimal inhibition of bacterial growth was observed in symmetric, biscationic structures; minimum inhibitory concentration (MIC) values measured as low as 0.5 μM against both Gram-positive and Gram-negative bacteria for the compound PMQ-11,11. Electrochemical analysis demonstrated the redox properties of the dialkyl 3,3′- and 3,4′-bipyridinium amphiphiles to be distinct from those of the 4,4′-bipyridinium isomer. Thus MQ and PMQ amphiphiles maintain the strong antibacterial activity of the PQ isomers, but show promise for reduced ROS toxicity.     

3-(3-Azido-2,3-Dideoxy-β-D-erythro pentofuranosyl)-thymine from 3′-Azido-3′-deoxythymidine (AZT). An Intriguing Rearrangement

Abstract

During the course of preparation of 3′-azido-3′-deoxythymidine (AZT), we observed consistent formation of an isomer of AZT (2-4%) which was isolated and the structure established as 3-(3-azido-2,3-dideoxy-β-D-ezythro pentofuranosyl)thymine. In a more detailed study, this rearrangement was found to occur during the treatment of 2,3′-anhydro-5′-O-tritylthymidine (1) with LiN₃ in aqueous DMF.     

2′-O-MODIFIED OLIGORIBONUCLEOTIDES WITH TERMINAL 3′-3′-INTERNUCLEOTIDE LINKAGE AND THEIR DERIVATIVES

A high RNA binding affinity and nuclease resistance of 2′-O-modified (2′-O-methyl, 2′-O-tetrahydropyranyl) oligoribonucleotides containing the “inverted” T at the 3′-end have been shown. The synthesis and properties of new photoactivatable perfluoroarylazide derivatives of these oligoribonucleotides are discussed.     

New 3′-3′ Linkers for Alternate Strand Triplex Forming Oligonucleotides

Abstract

New solid supports, functionalized with suitably protected 1,2,3-propanetriol and cis,cis-1,3,5-cyclohexanetriol, were efficiently prepared and used in the standard automated synthesis of 3′-3′ linked ODNs for triplex formation experiments.     

3-β-d-erythrofuranosyl-1-phenylpyrazolo[3,4-b]quinoxaline,a new C-nucleoside analog

Dehydration of the hydroxyalkyl chain of 1-phenyl-3-(d-arabino-tetritol-1-yl)pyrazolo[3,4-b]quinoxaline gave the C-nucleoside 3-β-d-erythrofuranosyl-1-phenyl-pyrazolo[3,4-b]quinoxaline (2) in 82% yield. The structure, and the configuration at the anomeric carbon atom, of 2 were elucidated by periodate oxidation, c.d. and n.m.r. spectroscopy, and mass spectrometry. N.m.r.-spectral and c.d. studies revealed that, due to the large size of the heterocyclic base, compound 2 is formed by inversion in the configuration or C-1 of the side chain. The mechanism of the dehydrative cyclization with inversion is discussed.     

SYNTHETIC STUDY OF 3′-α-FLUORO-2′,3′-DIDEOXYGUANOSINE

A synthetic method was established for 3′-α-fluoro-2′,3′-dideoxyguanosine 1 from guanosine 2 in 27% overall yield and 6 steps. A byproduct 6a of fluorination was identified by NMR studies, its presence strongly supporting our supposition that the fluorination itself proceeded via a bromonium cation.     

Synthesis and Properties of Phosphorylated 3′-O-β-D-Ribofuranosyl-2′-deoxythymidine

Abstract

A strategy was developed for the synthesis of 3′-O-β-D-ribofuranosyl 2′-deoxythymidine derivatives using three different protecting groups, which allows the synthesis of a phosphoramidite building block for oligonucleotide synthesis. Likewise the 5′-O- and 5″-O-phosphorylated analogues were synthesized and their conformation was determined using NMR spectroscopy.     

Oligodeoxyribonucleotides Covalently Linked via Nucleic Bases with 3′-5′ and 5′-5′ Polarities

Abstract

The solid-phase preparation of oligodeoxyribonucleotides covalently linked via nucleic bases with normal (3′-5′) or inverted (5′-5′) polarities is reported. The key-step of these syntheses is the preparation of the tethered dimers.