Synthesis of sucrose epoxides,partial de-esterification of 1′,2:4,6-di-O-isopropylidenesucrose tetra-acetate,and selective tosylation of 3,6′-di-O-acetyl-1′,2:4,6-di-O-isopropylidenesucrose

Selective de-esterification of 1′,2:4,6-di-O-isopropylidenesucrose tetra-acetate² (1) with methanolic ammonia at ?10° gave an inseparable mixture (2+3) of the 3,4′,6′- and 3,3′,6′-triacetates and also the 4,6′-diacetate 4. When the reaction was performed at 5°, it gave 4, the 4-acetate 8, and the parent diacetal 9. These derivatives allow selective reaction at hydroxyl groups in sucrose, in particular at HO-3′ and, HO-4′, not hitherto possible. Mesylation of 4 gave the 3′,4′-dimesylate 7, which, on treatment with aqueous acetic acid followed by acetylation, afforded 3′,4′-di-O-mesylsucrose hexa-acetate (11). Treatment of 11 with sodium methoxide in methanol at 70° for 1 min gave the ribo-3′,4′-epoxide 12 as the minor, and the lyxo-3′,4′-epoxide 13 as the major, product. Selective tosylation of 4 gave the 3',4'-ditosylate 14 (3.7%), 4′-tosylate 15 (3.1%), and 3'-tosylate 16 (31%), indicating the order of reactivity HO-3′>HO-4′ in 4. De acetalation of 15 and 16 followed by acetylation gave the hepta-acetates of 4′- and 3′-O-tosylsucrose, respectively, which were converted into the respective epoxides, 13 and 12, by methanolic sodium methoxide.     

Synthesis and some reactions of methyl 4,6-O-benzylidene-2,3-dideoxy-2-phenylazo-β-d-erythro-hex-2-enopyranoside

Methyl 4,6-O-benzylidene-2,3-dideoxy-2-phenylazo-β-d-erythro-hex-2-enopyranoside has been synthesised, and its addition reactions with methoxide, azide, hydride, and deuteride ions have been studied. Comment is made on the stereochemistry of addition reactions of 2- and 3-phenylazo derivatives of methyl 4,6-O-benzylidene-2,3-dideoxy-d-hex-2-enopyranosides.     

Chiral 1′, 2′-Seco-Nucleosides: Synthesis of D and L-Threitol-2′-O-Methylenyl Nucleosides

Abstract

1′, 2′-Seco-nucleoside derivatives of adenine, cytosine, guanine and thymine with a D or L-threitol side-chain configuration have been synthesized from D or L dimethyl tartarate respectively. Biological evaluation of the four enantiomeric pairs of nucleosides revealed they were inactive against various viruses in cell cultures.     

Synthesis of 1′,2′-Seco-nucleoside Analogues of AZT

Abstract

1′,2′-Seco-AZT (3) and its 3′R,4′S diastereomer (19) were prepared and evaluated as antiviral agents. The chiral, acyclic side chains of these thymine acyclonuleosides were derived from D-isoascorbic acid. The two AZT analogues, 3 and 19, were screened against HIV, other RNA viruses, and two DNA viruses and they were found to be inactive.     

Nucleosides VIII: 1 Synthesis of 2′, 3′-Dideoxy- and 2′, 3′-Didehydro-2′, 3′-Di Deoxyisoguanosine as Potential Antiretroviral Agents

Abstract

2′, 3′-Didehydro-2′, 3′-dideoxyisoguanosine (2) and 2′, 3′- dideoxyisoguanosine (3) have been synthesized by utilizing the Corey-Winter approach starting from isoguanosine. The 6-amino and 5′-hydroxy biprotected isoguanosine derivative was converted to the corresponding 2′, 3′- thionocarbonate, which was heated with triethyl phosphite to afford the 2′,3′- olefinic product. Either a tert-butyldimethylsilyl or a 4, 4′-dimethoxytrityl group was used in the protection of 5′-hydroxy function. Compounds 2 and 3 were found inactive against human immunodeficiency virus (HIV), human cytomegalovirus (HCMV), and herpes simplex virus type 1 (HSV-1).

     

Synthesis of 2′,3′-Dideoxyribavirin

Abstract

A synthesis of 1-(2,3-dideoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′,3′-dideoxyribavirin, ddR) is described. Glycosylation of the sodium salt of 1,2,4-triazole-3-carbonitrile (5) with 1-chloro-2-deoxy-3,5-di-0-p-toluoyl-α-D-erythro-pentofuranose (1) gave exclusively the corresponding N-1 glycosyl derivative with β-anomeric configuration (6), which on ammonolysis provided a convenient synthesis of 2′-deoxyribavirin (7). Similar glycosylation of the sodium salt of methyl 1,2,4-triazole-3-carboxylate (2) with 1 gave a mixture of corresponding N-1 and N-2 glycosyl derivatives (3) and (4), respectively. Ammonolysis of 3 furnished yet another route to 7. A four-step deoxygenation procedure using imidazolylthiocarbonylation of the 3′-hydroxy group of 5′-0-toluoyl derivative (9a) gave ddR (11). The structure of 11 was proven by single crystal X-ray studies. In a preliminary in vitro study ddR was found to be inactive against HIV retrovirus.     

Synthesis of 1′,2′-methano-2′,3′-dideoxynucleosides as potential antivirals

The synthesis of constrained nucleosides has become an important tool to understand the SAR in the interaction between biological and synthetic nucleotides in the context of antisense oligonucleotide therapy. The incorporation of a cyclopropane into a furanose ring of a nucleoside induces some degree of constrain without affecting significantly the steric environment of a nucleoside. Here, we report a new, short and stereocontrolled synthesis of two constrained nucleosides analogues, 1′,2′- methano-2′,3′-dideoxyuridine 9, and the corresponding cytidine analog 12. X-ray crystallography revealed that the furanose ring in the constrained uridine and cytidine analogues was flattened with virtual loss of pseudorotation. The phosphoramidate esters of the novel constrained uridine and cytidine nucleosides, intended as prodrugs, were tested in cell-based assays for viral replication across the herpes virus family and HIV inhibition courtesy of Merck laboratories, Rahway. They were also tested in antiproliferative assays against colorectal and melanoma cell lines. Unfortunately, none of the compounds showed activity in these assays.     

Synthesis,evaluation of anti-HIV-1 and anti-HCV activity of novel 2′,3′-dideoxy-2′,2′-difluoro-4′-azanucleosides

A series of 2′,3′-dideoxy-2′,2′-difluoro-4′-azanucleosides of both pyrimidine and purine nucleobases were synthesized in an efficient manner starting from commercially available L-pyroglutamic acid via glycosylation of difluorinated pyrrolidine derivative 15. Several 4′-azanucleosides were prepared as a separable mixture of α- and β-anomers. The 6-chloropurine analogue was obtained as a mixture of N⁷ and N⁹ regioisomers and their structures were identified based on NOESY and HMBC spectral data. Among the 4′-azanucleosides tested as HIV-1 inhibitors in primary human lymphocytes, four compounds showed modest activity and the 5-fluorouracil analogue (18d) was found to be the most active compound (EC₅₀ = 36.9 μM) in this series. None of the compounds synthesized in this study demonstrated anti-HCV activity.     

New Approach to the Synthesis of 2′,3′-dideoxyadenosine and 2′,3′-Dideoxyinosine

Abstract

A new approach to the synthesis of 2′,3′-dideoxyadenosine and 2′,3′-dideoxyinosine based on deoxygenation of 2′,3′-di-O-mesylnucleosides was developed.     

Synthesis and Reactions of Some 3′,4′-Unsaturated 2′,3′-Secouridine Analogues

Abstract

2′,3′-Dibromo-2′,3′-dideoxy-5′-O-trityl-2′,3′-secouridine (8) with sdKF gave the 3′,4′-didehydro-2,2′-anhydro nucleoside 9, which was deprotected to 10. Hydrolysis of 9 gave 3′,4′-didehydro-3′-deoxy-5′-O-trityl-2′,3′-secouridine (11a). Similarly, compound 9 with pyridinium halides gave the corresponding 2′-deoxy-2′-halo nucleosides (11b-d). Compound 11d with azide ion gave 2′-azido analogue 11e. Compound 9 with an excess amount of azide ion gave the 2′-azido triazole (13).     

The enantiomers of the 1′,6′-isomer of neplanocin A: Synthesis and antiviral properties

Both enantiomers of 1′,6′-isoneplanocin have been prepared from a common substituted cyclopentane epoxide in 7 steps. Both compounds were subjected to DNA and RNA viral assessments with moderate to high activity found for both towards human cytomegalovirus, measles, Ebola, norovirus, and dengue. The D-like congener also showed vaccinia and HBV effectiveness. In many of the other antiviral assays both compounds showed cytotoxicity making, in some cases, an EC₅₀ determination not possible. The S-adenosylhomocysteine hydrolase inhibitory effects showed the D-like target to be equal that of neplanocin itself and better than 3-deazaneplanocin whereas the L-like analogue was 13 to 30 times less inhibitory than 3-deazaneplanocin and neplanocin, respectively.     

1′, 2′-Seco-2′,3′-Dideoxynucleoside Analogues: Synthesis and Antiviral Evaluation of Racemic Trans-[1′, 5′-Dihydroxy 3′, 4′-methylenylpent-2′-oxy)methyl] Nucleosides

Abstract

Reaction of (±)but-3-en-1,2-diol (3) with ethyl diazoacetate afforded two cyclopropyl compounds (5) and (6). Their relative trans stereochemistry at C-2 and C-3 has been determined by high-field and computational NMR spectroscopy. (±)Trans-1-(1′,5′-dihydroxy-3′,4′-methylenyl-pent-2′-oxy)methyl]thymine (1d) or -cytosine (1b) and (±)trans-9-(1′,5′-dihydroxy-3′,4′-methylenylpent-2′-oxy)-methyl]adenine (la) or -guanine (1c) have been obtained through a regiospecific alkylation procedure and their antiviral evaluation is reported.     

Synthesis and Evaluation of Anti-HIV-1 and Antitumor Activity of 2′,3′-didehydro-2′,3′-dideoxy-3-deazaadenosine, 2′,3′-dideoxy-3-Deazaadenosine and Some 2′,3′-dideoxy-3-deaza-adenosine 5′-dialkyl Phosphates1

Abstract

- The 4-amino-1-(2.3-dideoxy-β-D-glycero-pent-2-enofurano-syl)-1H-irnidazo[4,5-c]pyridine (1) and 4-amino-1-(2,3-dideoxy-β-D-gfycero-pentofuranosyl)-1H-imidazo[4,5-c]pyridine (2), 3-deaza analogues of the anti-HIV agents 2′.3′-didehydro-2′,3′-dideoxyadenosine (d4A) and 2′,3′-dideoxy-adenosine (ddA), have been synthesized. The reaction of 3-deazaadenosine (3) with 2-acetoxyisobutyryl bromide yielded a mixture of cis and trans 2′,3′-ha-lo acetates which was convertcd into olefinic nucleoside (1) on treatment with a Zn/Cu couplc and then with methanolic ammonia. The 2′,3′-dideoxy-3-deazaadenosine (2) was obtained by catalytic reduction of 1. A number of phosphate triester derivatives of 2 have also been prepared. The diethyl-, dipropyl- and dibutylpliospliates 7a-c and 3-deazaadenosine have shown anti-HIV activity at non-cytotoxic doses. Compounds 7a-c have also shown significant cytostatic activity against murine colon adenocarcinoma cells.     

Synthesis of 2′,3′-Didehydro-2′,3′-dideoxyisoinosine and Oxidation of Fluorescent 2-Hydroxypurine Nucleosides by Xanthine Oxidase

Abstract

The syntheses of 2′,3′-didehydro-2′,3′-dideoxyisoinosine (d4isoI, 4) as well as 7-deaza-2′,3′-didehydro-2′,3′-dideoxyisoinosine (d4c₇isoI, 5) are described. Compounds 4 and 5 show both strong fluorescence. Compound 4 is oxidized by xanthine oxidase to give the corresponding xanthine 2′,3′-dideoxy-2′,3′-didehydronucleosides. A preparative chemo-enzymatic synthesis of 2′-deoxyxanthosine (3) is described.     

2′,3′-Dideoxyuridine triphosphate conjugated to SiO2 nanoparticles: Synthesis and evaluation of antiproliferative activity

A conjugate of triphosphorylated 2′,3′-dideoxyuridine (ddU) with SiO₂ nanoparticles was obtained via the CuAAC click chemistry between a γ-alkynyl ddU triphosphate and azido-modified SiO₂ nanoparticles. Assessment of cytotoxicity in human breast adenocarcinoma MCF7 cells demonstrated that ddU triphosphate conjugated to SiO₂ nanoparticles exhibited a 50% decrease in cancer cell growth at a concentration of 183?±?57?µg/mL, which corresponds to 22?±?7?µM of the parent nucleotide, whereas the parent nucleoside, nucleotide and alkynyl triphosphate precursor do not show any cytotoxicity. The data provide an example of remarkable potential of novel conjugates of SiO₂ nanoparticles with phosphorylated nucleoside analogues, even those, which have not been used previously as therapeutics, for application as new anticancer agents.     

Synthesis and biophysical properties of 5′-thio-2′,4′-BNA/LNA oligonucleotide

Phosphorothioate modification of oligonucleotides is one of the most promising chemical modifications in nucleic acid therapeutics. Structurally similar 5′-thio or phosphorothiolate-modified nucleotides, in which the 5′-bridging oxygen atom is replaced with a sulfur atom, are attracting attention and gaining importance in oligonucleotide-based research. In our present study, we synthesized 5′-thio-2′,4′-BNA/LNA monomers bearing thymine or 5-methylcytosine nucleobase. The 5′-thio-2′,4′-BNA/LNA monomers were successfully incorporated into target oligonucleotides, and their nuclease stability and binding affinity with complementary strands were evaluated.     

Synthesis of Isoxazolidino Analogues of 2′,3′-Dideoxynucleosides

Abstract

The complete set of the 4′-aza analogues of 2′,3′-dideoxynucleosides was synthesized by cycloaddition of N-tetrahydropiranyl or N-trityl methylene nitrones on suitably protected vinyl nucleobases. The convertible nucleoside approach was used in the preparation of cytosine and 5-methyl cytosine analogues.     

Improved Synthesis of 2′-Fluoro-2′-Deoxyadenosine and Synthesis and Carbon-13 NMR Spectrum of Its 3′,5′-Cyclic Phosphate Derivative1

Abstract

Some improvements were made on synthetic method for 2′-fluoro-2′-deoxyadenosine (11). Thus 11 was obtained in an overall yield of 9.3% starting from adenosine. 2′-Fluoro-2′-deoxyadenosine 3′,5′-cyclic phosphate (13), an analogue of cAMP, was synthesized from 11. The carbon-13 NMR spectrum was measured. The sugar carbon signals can be unambiguously assigned since the C1′ C2′ and C3′ have different ¹³C-¹⁹F coupling constants. Comparison of the data with those of other 3′,5′-cyclic phosphate derivatives confirms the assignments of C3′ and C4′ signals previously proposed by us.     

Synthesis of 1-O-(2′,4′-Dichlorophenoxyacetyl)-d-glucopyranose

1-O-Glucosyl esters of 2,4-dichlorophenoxyacetic acid (2,4-D) were easily prepared from 4,6-O-benzylideneglucose. The configuration of 1-O-ester linkage was affected by pH at the end of the reaction, that is, β-type was a major product at a neutral or acidic condition and α-type at an alkaline condition. Both of the anomers showed the same biological activities as sodium salt of 2,4-D.     

Synthesis of Novel 2′,3′-Didehydro-2′,3′-dideoxyinosine Phosphoramidate Prodrugs and Evaluation of their Anticancer Activity

An efficient synthesis of 4-chlorophenyl N-alkyl phosphoramidates of 2?′,3?′-didehydro-2?′,3?′-dideoxyinosine employing 4-chlorophenyl phosphoroditetrazolide as a phosphorylating agent is reported. Improved method for the synthesis of 2?′,3?′-didehydro-2?′,3?′-dideoxyinosine starting from inosine is also described. The synthesized phosphoramidates 11–18 were examined for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB), and breast (MCF-7) employing sulforhodamine B assay. The highest activity in all investigated cancer cell lines was displayed by phosphoramidate 13 with N-n-propyl substituent.