Unsaturated Nucleosides Research Articles

An alternative method for the synthesis of 2′-halogeno-1′,2′-unsaturated uridine derivatives through syn-elimination of pivalic acid of 2′-halogeno- 2′-deoxy-1′-pivaloyloxyuracil nucleoside: preparation of its 2′-C-branched nucleosides

An alternative method for the preparation of 2′-bromo- (5b) and 2′-iodo- (5c) 1′,2′-unsaturated uracil nucleosides has been developed. The protocol was on the basis of the syn-elimination of pivalic acid from 2′-bromo-(7a,b) and 2′-iodo-(9a,b) 1′-pivaloyloxy-2′-deoxyuridine derivatives, which were derived from the halo-pivaloyloxylation of 3′,5′-bis-O-TBDMS-1′,2′-unsaturated uridine 1. Compounds 5b and 5c were shown to serve as versatile synthons for the respective 2′-C-branched 1′,2′-unsaturated uracil nucleosides, through palladium-catalyzed cross-coupling or halogen-lithium exchange reactions.

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates.

To synthesize nucleoside and oligosaccharide derivatives, we often use a glycosylation reaction to form a glycoside bond. Coupling reactions between a nucleobase and a sugar donor in the former case, and the reaction between an acceptor and a sugar donor of in the latter are carried out in the presence of an appropriate activator. As an activator of the glycosylation, a combination of a Lewis acid catalyst and a hypervalent iodine was developed for synthesizing 4’-thionucleosides, which could be applied for the synthesis of 4’-selenonucleosides as well. The extension of hypervalent iodine-mediated glycosylation allowed us to couple a nucleobase with cyclic allylsilanes and glycal derivatives to yield carbocyclic nucleosides and 2’,3’-unsaturated nucleosides, respectively. In addition, the combination of hypervalent iodine and Lewis acid could be used for the glycosylation of glycals and thioglycosides to produce disaccharides. In this paper, we review the use of hypervalent iodine-mediated glycosylation reactions for the synthesis of nucleosides and oligosaccharide derivatives.

ChemInform Abstract: The Convenient Synthesis of Unsaturated Nucleoside Analogues in Water under Microwave Irradiation.

A convenient method for the regioselective synthesis of unsaturated nucleoside analogs in water under microwave irradiation was developed. All pyrimidine and purine nucleoside derivatives were exclusively alkylated at N1 and N9 respectively in good to excellent yields. In addition, this system could tolerate a broad range of functional groups, such as chloro, bromo, iodo, alkyl, amino, and hydroxyl groups. More importantly, the reaction scale could be enlarged to 50 mmol which made this route attractive for industrial application.

The Convenient Synthesis of Unsaturated Nucleoside Analogues in Water under Microwave Irradiation

ABSTRACTA convenient method for the regioselective synthesis of unsaturated nucleoside analogs in water under microwave irradiation was developed. All pyrimidine and purine nucleoside derivatives were exclusively alkylated at N1 and N9 respectively in good to excellent yields. In addition, this system could tolerate a broad range of functional groups, such as chloro, bromo, iodo, alkyl, amino, and hydroxyl groups. More importantly, the reaction scale could be enlarged to 50 mmol which made this route attractive for industrial application.

Unsaturation: An Important Structural Feature to Nucleosides’ Antiviral Activity

In the search of effective, selective and nontoxic antiviral agents, a variety of nucleoside analogues have been synthesized, with different functionalities in the carbohydrate moiety and/or the heterocyclic base. Nucleoside analogues bearing double or triple bonds are recognized as an important class of biologically active compounds and appear to be prominent drugs in the management of several viral infections, including HSV, HIV, HBV, HCV and HCMV. Currently, unsaturated nucleoside mimetics, such as stavudine, abacavir and entecavir have been approved for the treatment of viral infections, while elvucitabine and β-L-2´-F-d4C are in clinical trials. The purpose of this review is to give an update of the recent developments on nucleosides and nucleoside analogues with unsaturation, in both cyclic and acyclic forms, which possess promising therapeutic potential, mainly antiviral. It covers analogues with ring sizes from three to six and provides useful data, aiming at enhancing chemical reactivity as a result of the sugar and base conformations. Keywords: Acyclic, antiviral, base modified, carbocyclic, exomethylene, TSAO, unsaturated nucleosides.

ChemInform Abstract: Stereoselective Preparation of 1‐[5‐O‐(tert‐Butyldimethylsilyl) ‐2,3‐dideoxy‐3‐iodo‐β‐D‐threo‐pentofuranosyl]thymine from Thymidine: An Efficient Entry to 3′,4′‐Unsaturated Nucleoside.

AbstractThe title 3′,4′‐unsaturated nucleoside (IV) may be used for the preparation of 4′‐branched derivatives.

ChemInform Abstract: A Regiospecific Synthesis of Unsaturated Nucleosides, Carbohydrates, and Other Olefins.

ChemInform Abstract: A Regiospecific Synthesis of Unsaturated Nucleosides, Carbohydrates, and Other Olefins.

ChemInform Abstract: Selenoxide Elimination for the Synthesis of Unsaturated Sugar Uracil Nucleosides.

ChemInform Abstract: Selenoxide Elimination for the Synthesis of Unsaturated Sugar Uracil Nucleosides.

Synthesis and anti-HIV-1 evaluation of phosphonates which mimic the 5′-monophosphate of 4′-branched 2′,3′-didehydro-2′,3′-dideoxy nucleosides

Synthesis of the 4′-ethynyl and 4′-cyano phosphonates 8– 11, which mimic the 5′-monophosphate of 4′-branched 2′,3′-didehydro-2′,3′-dideoxy nucleosides, was investigated by employing the 3′,4′-unsaturated nucleosides ( 13 and 28) as the starting material. The synthesis was initiated by the electrophilic addition of NIS/(EtO) 2P(O)CH 2OH to these unsaturated nucleosides. After introduction of the 2′,3′-double bond, the 4′-hydroxylmethyl group of the resulting adducts was transformed into the ethynyl or cyano group. While the 4′-cyano phosphonates 9 and 11 were not sufficiently stable to be isolated, the 4′-ethynyl counterparts ( 8 and 10) were obtained as their mono-ammonium salts. The adenine derivative 8 showed almost comparable anti-HIV-1 activity to that of d4T.

Antiviral Unsaturated Nucleosides

In the search for effective, selective and nontoxic antiviral agents, a variety of nucleoside analogues have been synthesized, with different functionalities in the carbohydrate moiety. Unsaturated nucleoside analogues are recognized as an important class of biologically active compounds and appear to be prominent drugs in the management of several viral infections, including HSV, HIV, HBV, HCV and HCMV infections. Currently, unsaturated nucleoside mimetics, such as stavudine, abacavir and entecavir have been approved for the treatment of viral infections, while elvucitabine and β-L-2β- F-d4C are in clinical trials. The purpose of this review is to give an update of the recent developments on unsaturated nucleoside and nucleoside analogues, in both cyclic and acyclic forms, which possess promising therapeutic potential, mainly antiviral. It covers analogues with ring sizes from three to six and provides useful data, in the aim to enhance chemical reactivity or to study the fixation of the sugar conformation.

The Novel unsaturated acyclic nucleoside analogues: cytostatic and antiviral activity evaluations

The novel pyrimidine (3-6) and purine (12-19) acyclic nucleoside analogues containing (Z) 4-amino or 4-aminohydrochloride-2-butenyl side chain (Fig.) were synthesized to evaluate their antiviral and cytostatic activity potency.

Addition of Difluorocarbene to 3‘,4‘-Unsaturated Nucleosides: Synthesis of 2‘-Deoxy Analogues with a 2-Oxabicyclo[3.1.0]hexane Framework1

Treatment of protected 2'-deoxy-3',4'-unsaturated nucleosides derived from adenosine and uridine with difluorocarbene [generated from bis(trifluoromethyl)mercury and sodium iodide] gave fused-ring 2,2-difluorocyclopropane compounds. Stereoselective alpha-face addition to the dihydrofuran ring resulted from hindrance by the protected beta-anomeric nucleobases. A protected uracil compound was converted smoothly into the cytosine derivative via a 4-(1,2,4-triazol-1-yl) intermediate. Removal of the protecting groups gave new difluorocyclopropane-fused nucleoside analogues. The solid-state conformation of the nearly planar furanosyl ring in the uracil compound had a shallow 2E pucker, and a more pronounced 1E conformation was present in the furanosyl ring of the cytosine derivative.

Addition of Difluorocarbene to 4‘,5‘-Unsaturated Nucleosides: Synthesis and Deoxygenation Reactions of Difluorospirocyclopropane Nucleosides1

Synthetic routes to 4'-(2,2-difluorospirocyclopropane) analogues of adenosine, cytidine, and uridine are described. Treatment of 2',3'-O-isopropylidene-4',5'-unsaturated compounds derived from adenosine and uridine with difluorocarbene (generated from PhHgCF3 and NaI) gave diastereomeric mixtures of the 2,2-difluorospirocyclopropane adducts. Stereoselectivity resulting from hindrance by the isopropylidene group favored addition at the beta face. Removal of base and sugar protecting groups gave new difluorospirocyclopropane nucleoside analogues. The protected uridine analogue was converted into its cytidine counterpart via a 4-(1,2,4-triazol-1-yl) intermediate. Stannyl radical-mediated deoxygenation of the 3'-O-TBS-2'-thionocarbamate derivatives gave the 2'-deoxy products of direct hydrogen transfer. In contrast, identical treatment of the 2'-O-TBS-3'-thionocarbamate isomers resulted in opening of the vicinal difluorocyclopropane ring upon generation of a C3' radical followed by homoallylic hydrogen transfer to give 4'-(1,1-difluoroethyl)-3',4'-unsaturated nucleoside derivatives. Structural aspects and biological effect considerations are discussed.

Synthesis and Anti-HIV Activity of β-D-3′-Azido-2′,3′-unsaturated Nucleosides and β-D-3′-Azido-3′-deoxyribofuranosylnucleosides

Since the discovery of 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) as potent and selective inhibitors of the replication of human immunodeficiency virus (HIV), there has been a growing interest for the synthesis of 2′,3′-didehydro-2′,3′-dideoxynucleosides with electron withdrawing groups on the sugar moiety. Here we described an efficient method for the synthesis of such nucleoside analogs bearing structural features of both AZT and d4T. The key intermediate, 3-azido-1,2-bis-O-acetyl-5-O-benzoyl-3-deoxy-D-ribofuranose, 5 was synthesized from commercially available D-xylose in five steps, from which a series of pyrimidine and purine nucleosides were synthesized in high yields. The resultant protected nucleosides were converted to target nucleosides using appropriate chemical modifications. The final nucleosides were evaluated as potential anti-HIV agents.

Mechanism of Anti-Human Immunodeficiency Virus Activity of β- d -6-Cyclopropylamino-2′,3′-Didehydro-2′,3′-Dideoxyguanosine

To better understand the importance of the oxygen in the ribose ring of planar unsaturated nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2',3'-didehydro-2',3'-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metabolism, antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1 +/- 0.1 microM while showing 50% inhibition of cell viability at 84.5 microM. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-associated mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metabolism and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2'-deoxycoformycin, implying that the antiviral activity is due to its metabolism to the 2'-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chemical and potentially enzymatic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2',3'-dideoxycytidine and 2',3'-didehydro-3'-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability observed in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.

Concise Synthesis and Antiviral Activity of Novel Unsaturated Acyclic Pyrimidine Nucleosides

Novel acyclic nucleoside analogues were designed and synthesized as open-chain analogues of neplanocin A. The coupling of the allylic bromide with pyrimidine bases using cesium carbonate afforded a series of novel acyclic nucleosides. The synthesized compounds 15–22 were evaluated for their antiviral activity against various viruses such as HIV, HSV-1, HSV-2, and HCMV.

Concise Synthesis and Antiviral Activity of Novel Unsaturated Acyclic Pyrimidine Nucleosides

Concise Synthesis and Antiviral Activity of Novel Unsaturated Acyclic Pyrimidine Nucleosides

Chemical Modification of the Sugar Moiety of Pyrimidine Nucleosides via a 4’,5’-Epoxyuridine Intermediate

The reaction of 4',5'-unsaturated nucleoside (5) with m-CPBA provided different products depending on the solvent. 4',5'-Epoxynucleoside (6) was generated as a key intermediate although 6 was not stable enough to isolate and further reaction progressed. When the reaction was performed in CH 2 Cl 2 , 2,4'-cyclonucleoside (7) and 4'-ketonucleoside (8) were obtained. On the other hand, 4'-alkoxy derivatives (9 and 11) together with their epimers (10 and 12) were aquired as a mixture by the nucleophilic attack of alcohol.

Synthesis and Anti‐HIV Activity of 4′‐Cyano‐2′,3′‐didehydro‐3′‐deoxythymidine

A new anti‐HIV agent 4′‐cyano‐2′,3′‐didehydro‐3′‐deoxythymidine (9) was synthesized by allylic substitution of the 3′,4′‐unsaturated nucleoside 14, having a leaving group at the 2′‐position, with cyanotrimethylsilane in the presence of SnCl4. Evaluation of the anti‐HIV activity of 9 showed that this compound is much less potent than the recently reported 2′,3′‐didehydro‐3′‐deoxy‐4′‐(ethynyl)thymidine (1).

Stereoselective synthesis of 4'-carbon-substituted xylofuranosyladenines

Epoxidation of 2',5'-bis-O-silyl-protected N6-pivaloyl-3',4'-unsaturated adenine nucleosides (1, 2 and 3) with dimethyldioxirane uniformly proceeded face-selectively to give the respective 3',4'-beta-epoxides (4, 5 and 6). Ring cleavage of these epoxides examined with Me3Al in CH2Cl2 showed that the TBDMS (4) or TES (5) protected epoxide gave the desired 4'-alpha-methylated product (8 or 10) as the major stereoisomer, while use of the TBDPS protected epoxide (6) resulted in reverse stereoselectivity. Reactions of 4 with other organoaluminum reagents were also carried out.