Unsaturated Nucleosides Research Articles

Reactions Of 2′-Deoxy-2′-halouridines andO2,2′-Cyclouridine with Lithium Dialkylamides: Formation of 1′,2′-Unsaturated Derivatives

Abstract Treatment of 2′-deoxy-2′-halouridine derivatives with lithium diisopropylamide (LDA) resulted in partial formation of the 1′,2′-unsaturated nucleosides, no lithiation being observed in the base moiety of the recovered starting material. Reactions of an O2,2′-cyclouridine derivative with LDA or lithium 2,2,6,6-tetramethyl-piperidide (LTMP) were also examined.

Novel method for the synthesis of 2',3'-unsaturated nucleosides from 2'(3')-acetoxy-3'(2')-halogeno derivatives by using sodium dithionite with viologen as a reductive elimination mediator.

Reductive elimination of vicinal acetylated halohydrins with Na 2 S 2 O 4 as the reducing agent and viologen as the reduction mediator in a two-phase water-organic system is described. 2',3'-Unsaturrated nucleosides such as 1-(5-O-acetyl-2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)adenine, -hypoxanthine and -uracil were obtained from 2'(3')-acetoxy-3'(2')-halogeno derivatives in good yields by meanes of this procedure

Synthesis of 5-Fluoro-1-(3-O-benzoyl-4, 6-dideoxy- β-L-GLYCERO-hex-3-enopyranos-2-ulosyl)uracil

Abstract Synthesis of the title compound, an unsaturated ketohexo-pyranosyl nucleoside of 5-fluorouracil is reported. It was prepared by oxidation of the corresponding dibenzoylhexopyranosyl nucleoside with pyridinium dichromate/molecular sieves system.

ChemInform Abstract: Preparation of 1‐(2,3‐Dideoxy‐β‐D‐glycero‐pent‐2‐enofuranosyl)thymine (d4T) and 2′,3′‐Dideoxyadenosine (ddA): General Methods for the Synthesis of 2′,3′‐Olefinic and 2′,3′‐Dideoxy Nucleoside Analogues Active Against HIV.

AbstractThree different synthetic routes for the production of the 2',3'‐unsaturated nucleoside (Va) are reported.

Synthesis of unsaturated 4′-azido pyranosyl thymines as potential antiviral and anti-HIV agents

Condensation of thymine with diacetyl-D-xylal and triacetyl-D-glucal afforded the unsaturated nucleosides 1, 6 and 7. After deacetylation and selective protection of the primary hydroxy groups in the case of the glucose derivatives, these compounds were either submitted to Mitsunobu reaction with hydrazoic acid to give the azides 4, 14 and 15, or oxidised with PDC–molecular sieves to give the unsaturated keto nucleosides 3, 12 and 13. Reduction of the azides 4, 14 and 15 afforded the amino derivatives 5, 18 and 19. Oxidation of the latter two compounds gave the aminouronate nucleosides 20 and 21. Preliminary testing on various virus models, including HIV, showed the ketones 3, 12 and 13 to be the most active compounds of this series.

A regiospecific synthesis of unsaturated nucleosides, carbohydrates and other olefins

Vicinal disubstituted nucleosides, carbohydrates and cyclohexane derivatives with a pair of radical leaving groups, such as chloro, bromo, phenoxythiocarbonyloxy, and imidazolylthiocarbonyloxy groups, have been successfully converted to the corresponding olefins in high yields (60–90%) without observed side products, by reaction with tri-n-butyltin hydride and azobisisobutyronitrile in an appropriate solvent.

Antiproliferative effects of 4',5'-unsaturated adenine nucleosides on leukemia L1210 cells in vitro.

Several 4',5'-unsaturated adenine nucleosides were shown to have antiproliferative activity against L1210 leukemia cells in vitro. The active nucleosides were cytotoxic to the L1210 cells as demonstrated by Trypan Blue uptake. The cytotoxicity was not induced by alterations in the ribonucleoside and deoxyribonucleoside triphosphate levels of the L1210 cells.

A dihydropyridine carrier system for sustained delivery of 2',3'-dideoxynucleosides to the brain.

The present study evaluates the utility of the dihydropyridine in equilibrium pyridinium salt redox system for the specific delivery and sustained release of a model 2',3'-dideoxynucleoside to the brain of mice as the initial effort in a search for agents that may prove effective in reversing the complicating neurological disorders of AIDS. The unsaturated nucleoside 2',3'-didehydro-2',3'-dideoxythymidine (1), which is effective in protecting ATH8 cells against the cytopathogenicity of HIV-1, was converted to the corresponding N-methyl-1,4-dihydronicotinate derivative, 4, in three steps. The 5'-O-nicotinate ester, 2, obtained by reaction of 1 with nicotinyl chloride, was converted in quantitative yield to the N-methylpyridinium salt 3 on treatment with MeI in acetone. Reduction of the latter with Na2S2O4 gave 4 in 50% yield. Pseudo-first-order rate constants for the oxidation of 4 to 3 were observed in plasma (k = 3.54 x 10(-5) s-1) and in homogenates of mouse liver (k = 9.2 x 10(-5) s-1) and brain (k = 8.85 x 10(-5) s-1). None of the chemical delivery system 4 could be detected in the brain of female BDF/1 mice at 1 h postinjection. The peak level of 3 in the brain occurred at 3 h with a half-life of 25 h. Both 1 and N-methylnicotinic acid (trigonelline, 5) were readily identified by HPLC in a brain homogenate derived from mice injected (25 mg/kg) with 4. TLC showed a low level penetration of mouse brain by 1 (0.44 microgram/g wet tissue) following injection of the corresponding labeled [methyl-3H]-2',3'-unsaturated nucleoside (25 mg/kg). The data indicate that 4 crosses the blood-brain barrier to be oxidized by cerebral tissue to the ionic structure 3, which is "locked therein". The sustained local release of a 2',3'-dideoxynucleoside, such as 1, from a chemical delivery system (4) represents a potentially useful approach to the treatment of AIDS dementia complex.

2′,3′-Dideoxyadenosine Analogs of the Nucleoside Antibiotics Tubercidin, Toyocamycin and Sangivamycin

Abstract Application of previously described methodologies, for the synthesis of 2′,3′-dideoxy-2′,3′-didehydro nucleosides from the parent ribonucleosides, to the antibiotics tubercidin (1), toyocamycin (6) and sangivamycin (10) has provided the corresponding 2′,3′-unsaturated nucleosides 4, 9, and 13. A reduction of the 2′,3′-unsaturated moiety has afforded the 2′,3′-dideoxynucleoside antibiotics 5, 14, and 15.

Structural Features of 2′,3′-Dideoxy-2′,3′-Didehydrocytidine, A Potent Inhibitor of the HIV (AIDS) Virus

Abstract The structure and conformation of 2′,3′-dideoxy-2′,3′-didehydrocytidine (2′,3′-dideoxycytidin-2′-ene, d4C), a potent inhibitor of the human immunodeficiency virus, was determined by X-ray crystallography. The nucleoside crystallizes in the orthorhombic space group P212121 with cell dimensions a = 8.603(1), b = 9.038(1), c = 25.831(2) A and with two independent molecules in the asymmetric unit (Z = 8). Atomic parameters were refined by full-matrix least squares to a final value of R = 0.033 for 2258 observed reflections. The molecules are quite flexible: in molecule A the glycosyl torsion angle (XCN) is 61.3° and the -CH2OH side chain is in the gauche + orientation while in molecule B XCN = 19.8° and the side chain is trans. The five-membered rings are slightly puckered (∼0.1 A), 04′ being endo in molecule A and exo in molecule B. A mechanism is proposed for the known instability of 2′,3′-unsaturated nucleosides.

Unsaturated Nucleoside Analogues: Synthesis and Antitumor Activity

Abstract Five classes of unsaturated nucleoside analogues were investigated as inhibitors of growth of murine leukemia L 1210 culture. The structural types include E ole-fins 1, Z-olefins 2, acetylene derivatives 3, allenes 4 and oxacyclopentenes 5. Compounds of the type 1-3 (X = Cl) were obtained by alkylation of the respective nucleic acid bases or 2-amino-6-chloropurine with E and Z-1,4-dichloro-2-butene or 1,4-di-chloro-2-butyne. Acid hydrolysis of intermediates 1, 2 and 3 (X = CI) led to the corresponding alcohols 1, 2 and 3 (X = OH). Chloroallene 4 (B = Ade, X = CI) was obtained by chlorination of adenallene (B = Ade, X = OH). Compounds of the type 5 were obtained by base-catalyzed cyclization of the respective 2-butynes. A prolonged hydrolysis of compound 2 (B = 2-amino-6-chloropurine, X = CI) gave tricyclic derivative 7. Similar cyclization of 2 (B = Ade, X = CI) afforded a 3, g-bridged adenine 8. Alcohol 2 (B = Ade, X = OH) is a poor substrate for adenosine deaminase as contrasted with compounds ...

ChemInform Abstract: An Improved Method for the Preparation of 2′,3′‐Unsaturated Nucleosides: Synthesis of Stereospecifically Labelled Ketonucleosides.

Abstract 2′,3′-Unsaturated nucleosides have been prepared in excellent yields under mild conditions by the condensation of acetylated glycals with purine or pyrimidine derivatives in the presence of trityl perchlorate. The synthesis of (α- and β-hex-2-enopyranosyl-4-ulose)theophylline nucleosides labelled at position 3′ with deuterium is described.

An improved method for the preparation of 2′,3′-unsaturated nucleosides: Synthesis of stereospecifically labelled ketonucleosides

2′,3′-Unsaturated nucleosides have been prepared in excellent yields under mild conditions by the condensation of acetylated glycals with purine or pyrimidine derivatives in the presence of trityl perchlorate. The synthesis of (α- and β-hex-2-enopyranosyl-4-ulose)theophylline nucleosides labelled at position 3′ with deuterium is described.

ChemInform Abstract: Synthesis and Biological Activity of Unsaturated Carboacyclic Purine Nucleoside Analogues.

Two new carboacyclic nucleoside analogues, 9-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]adenine (6) and 9-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]guanine (5), modeled on the unsaturated carbocyclic nucleoside analogue neplanocin A (2), have been synthesized and tested for antiviral activity against HSV-2 and, in the case of 6, for activity against influenza and in vitro inhibition of S-adenosylhomocysteine hydrolase. The synthesis was accomplished through the coupling of either adenine or the guanine precursor 2-amino-6-chloropurine (15) to the key intermediate 1-(benzyloxy)-2-[(benzyloxy)methyl]-4-chloro-2-butene (13). Debenzylation of the N-9 adenine adduct gave 6 directly, while the product of the debenzylation of the N-9 adduct of 15 when treated with sodium hydroxide gave the guanine analogue 5. The carboacyclic guanine analogue (5) exhibited significant antiviral activity against HSV-2 (VR = 1.5, MIC50 = 65.6 micrograms/mL), a level of activity that is superior to that of ara-A but inferior to that of acyclovir. The adenine analogue 6 was active against HSV-2 only at a very high dose; it was devoid of antiviral activity against influenza type A2, and it lacked inhibitory activity against S-adenosylhomocysteine hydrolase.

Synthesis and conformational analysis of the N1- and N3-5-fluorouracil nucleosides of 4-deoxyl- l- threo-hex-4-enopyranuronic acid

4′,5′-Unsaturated nucleosides are obtained by the action of 1,5-diazabicyclo-[5.4.0]undec-5-ene on N 1- and N 3-(methyl 2,3,4-tri- O-acetyl-β- d-glucopyranosyluronate)-5-fluorouracil. The 2 H 1 conformation of N 1- and N 3-(methyl 4-deoxy-α- l- threo-hex-4-enopyranosyluronate)-5-fluorouracil has been established by 1H-n.m.r. and c.d. methods. Interaction of the heterocyclic base and the double bond of the sugar moiety is demonstrated.

Isolation and identification of products in the reaction of 2-acetamido-3,4,6-tri- O-acetyl-1,5-anhydro-2-deoxy- d- arabino-hex-1-enitol with theophylline

Fusion of 2-acetamido-3,4,6-tri- O-acetyl-1,5-anhydro-2-deoxy- d- arabino-hex-1-enitol with theophylline, in the presence of boron trifluoride etherate as the catalyst, caused condensation to occur. This reaction afforded a variety of products of nucleosidic character, which were successively separated by repeated chromatography on silica gel. The structures of the products were determined, on the basis of X-ray crystallographic analysis (for three compounds) and by means of n.m.r.-spectral data and mass spectrometry, as the following: 7-(2-acetamido-4,6-di- O-acetyl-2,3-dideoxy-β- d- erythro-hex-2-enopyranosyl)theophylline, the corresponding α- and β- d- threo derivatives, and 7-(2-acetamido-6- O-acetyl-2,3-dideoxy-α- d- threo-hex-2-enopyranosyl)theophylline and its β anomer. In addition to these 2′,3′-unsaturated nucleosides having the base linked at C-1′, three products of a new type, having the base attached at C-4′, were also isolated: 7-(methyl 2-acetamido-6- O-acetyl-2,3,4-trideoxy-β- d- erythro-hex-2-enopyranosid-4-yl)theophylline, and the corresponding α- d- threo and α- d- erythro isomers. The correlation of the data obtained by X-ray structure analysis and proton nuclear magnetic spectroscopy, together with their application for the determination of configuration and conformation of these compounds, are discussed. It appears that the 1H-n.m.r. data alone do not suffice for unambiguous and correct structure determination for these classes of compounds.

Derivés chlorés de l'uridine: nouvelles voies d'accés commode au 1-(2,3-didésoxy-β- D- glycéro-pent-2-énofuranosyl)uracile (“uridinène”)

Treatment of 1-(2,3-anhydro-5- O-benzoyl-β- D-lyxofuranosyl)uracil with hydrogen chloride gave the 3-chloro- D- arabino analog, which was converted into the 2,3-dichloro- D- ribo analog ( 3) with the tetrachloromethane-triethyl phosphatetriphenylphosphine reagent. Free-radical reduction of 3 gave 1-(5- O-benzoyl-2,3-dideoxy-β- D- glycero-pent-2-enofuranosyl)uracil ( 4), which was debenzoylated to the free, unsaturated nucleoside (“uridinene”) by alkaline methanolysis (43 % overall yield). The same chlorinating reagent converted 5′- O-benzoyluridine into a mixture of the D- xylo analog of 3 with 1-(5- O-benzoyl-2-chloro-2,3-dideoxy-β- D- glycero-pent-2-enofuranosyl)uracil. Free-radical reduction of this mixture again gave 4, in 23% overall yield from 5′- O-benzoyluridine.

Synthesis and antitumor activity of cytosine and adenine nucleosides of unsaturated 5-(aminoacyl)aminopentofuranoses

Direct synthesis of the 1- and 9-(5-azido-2,3,5-trideoxy-β-D-glycero-pent-2-enofuranosyl) derivatives (3a and 3b) of cytosine and adenine, respectively, has been accomplished via treatment of the corresponding 2′,3′-unsaturated nucleosides (1a and 1b) with triphenylphosphine and carbon tetrabromide in the presence of lithium azide. Members of a new type of (aminoacyl)amino nucleoside, the 1- and 9-[5-(aminoacyl)amino-2,3,5-trideoxy-β-D-glycero-pent-2-enofuranosyl] derivatives of cytosine and adenine, respectively, have been obtained by condensation of the corresponding, unsaturated amino nucleosides with the active esters of several amino acid derivatives, followed by deprotection. These nucleosides were examined for in vivo antitumor activity against leukemia L-1210 and Sarcoma 180 (solid tumor) in mice; none of them exhibited antitumor activity against L-1210 in mice, but compounds 1a, 3a, and 1-[2,3,5-trideoxy-5-(L-methionyl)amino-β-D-glycero-pent-2-enofuranosyl]cytosine exhibited weak activity against Sarcoma 180 (solid tumor).

Synthesis of uracil and thymine nucleosides of unsaturated 5-(aminoacyl)aminopentofuranoses

Improved syntheses of 1-(2,3-dideoxy-β- d- glycero-pent-2-enofuranosyl)-uracil ( 5a) and -thymine ( 5b) have been achieved via treatment of the corresponding 3′,5′-oxetane with sodium hydroxide in hexamethylphosphoric triamide. The 2′,3′-unsaturated nucleosides ( 5a and 5b) were converted into 1-(5-amino-2,3,5-trideoxy-β- d- glycero-pent-2-enofuranosyl)-uracil ( 8a) and -thymine ( 8b), respectively. A new type of aminoacyl nucleoside, the 1-[5-(aminoacyl)amino-2,3,5-trideoxy-β- d- glycero-pent-2-enofuranosyl)-uracils and -thymines, has been obtained by condensation of 8a and 8b with the active esters of several amino acid derivatives followed by deprotection. These nucleosides were examined for in vivo antitumor activity against Sarcoma 180 (solid tumor). However, none of the compounds exhibited significant antitumor activity.

Synthetic electrochemical studies on nucleosides. 1. Novel method for the synthesis of 2',3'-unsaturated nucleosides via electrolysis

Synthetic electrochemical studies on nucleosides. 1. Novel method for the synthesis of 2',3'-unsaturated nucleosides via electrolysis