Carbocyclic Adenosine Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Antiviral Agents: Recent Advances

Abstract

Various carbocyclic analogues of adenosine, including aristeromycin (carbocyclic adenosine), carbocyclic 3-deazaadenosine, neplanocin A, 3-deazaneplanocin A, the 5′-nor derivatives of aristeromycin, carbocylic 3-deazaadenosine, neplanocin A and 3-deazaneplanocin A, and the 2-halo (i.e., 2-fluoro) and 6′-R-alkyl (i.e., 6′-R-methyl) derivatives of neplanocin A have been recognized as potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. This enzyme plays a key role in methylation reactions depending on S-adenosylmethionine (AdoMet) as methyl donor. AdoHcy hydrolase inhibitors have been shown to exert broad-spectrum antiviral activity against pox-, paramyxo-, rhabdo-, filo-, bunya-, arena-, and reoviruses. They also interfere with the replication of human immunodeficiency virus through inhibition of the Tat transactivation process.     

Synthesis,conformational study and antiviral activity of l-like neplanocin derivatives

The l-like enantiomer of 9-(trans-2′, trans-3′-dihydroxycyclopent-4′-enyl)-3-deazaadenine (DHCDA) (1), its 3-deaza-3-bromo derivative (3), and the conformational restricted methanocarba (MC) nucleoside analogues (2 and 4) were synthesized. X-ray crystal structures showed the L isomer MC analogue 4 adopts a similar North-like locked conformation as conventional D-MC nucleosides, while the DHCDA analogue 3 preferred south-like conformer. Compounds 1 and 4 showed potent antiviral activity against norovirus, while compound 2 and 3 were less potent or inactive. The conformational behavior of “sugar” puckering (north/south) and nucleobase orientation (syn /anti) may contribute to the antiviral activity differences. For compound 3, antiviral activity was also found against Ebola virus.     

John Montgomery's Legacy: Carbocyclic Adenosine Analogues as Sah Hydrolase Inhibitors with Broad-Spectrum Antiviral Activity

Ever since the S-adenosylhomocysteine (AdoHcy, SAH) hydrolase was recognized as a pharmacological target for antiviral agents (J. A. Montgomery et al., J. Med. Chem. 25:626–629, 1982), an increasing number of adenosine, acyclic adenosine, and carbocyclic adenosine analogues have been described as potent SAH hydrolase inhibitors endowed with broad-spectrum antiviral activity. The antiviral activity spectrum of the SAH hydrolase inhibitors include pox-, rhabdo-, filo-, arena-, paramyxo-, reo-, and retroviruses. Among the most potent SAH hydrolase inhibitors and antiviral agents rank carbocyclic 3-deazaadenosine (C-c³Ado), neplanocin A, 3-deazaneplanocin A, the 5′-nor derivatives of carbocyclic adenosine (C-Ado, aristeromycin), and the 2-halo (i.e., 2-fluoro) and 6′-R-alkyl (i.e., 6′-R-methyl) derivatives of neplanocin A. These compounds are particularly active against poxviruses (i.e., vaccinia virus), and rhabdoviruses (i.e., vesicular stomatitis virus). The in vivo efficacy of C-c³Ado and 3-deazaneplanocin A has been established in mouse models for vaccinia virus, vesicular stomatitis virus, and Ebola virus. SAH hydrolase inhibitors such as C-c³Ado and 3-deazaneplanocin A should in the first place be considered for therapeutic (or prophylactic) use against poxvirus infections, including smallpox, and hemorrhagic fever virus infections such as Ebola.     

Synthesis and Evaluation of Novel 6′,6′-Difluoro 5′-Deoxycarbocyclic Phosphonic Acid Nucleosides as Antiviral Agents

The authors describe highly efficient synthetic routes for the preparation of novel 6′,6′-difluoro 5′-deoxycarbocyclic phosphonic acid nucleosides from 1,4-dihydroxy-2-butene. The discovery that the 6′-fluorinated carbocyclic nucleoside (2, EC₅₀ = 0.16 μM) is a potent anti-HSV-1 agent led to the syntheses and biological evaluations of 6′-modified 5′-deoxyversions of carbocyclic phosphonate nucleosides. The synthesized nucleoside analogues 15, 18, 22, and 25 were tested for anti-HIV activity and for cytotoxicity. However, none of them showed significant anti-HIV-1 activity or cytotoxicity at concentrations up to 100 μM.     

Synthesis of novel 2-amino-4-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-4H-pyran-3-carbonitrile derivatives as antimicrobial and antioxidant agents

As a part of systematic investigation of synthesis and biological activities of indole analogues linked to various heterocyclic systems, we have synthesized new compounds viz., 2-amino-4-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-4H-pyran-3-carbonitriles (2a–i), 4,5-diamino-6-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-8-aryl-2-oxo-2,6-dihydrodipyrano [2,3-b:3,2-e]pyridine-3-carbonitriles (3a–i), 4-amino-5-(5′-substituted 2′-phenyl-1H-indol-3-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-ones (4a–i), 4-amino-5-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-thiones (5a–i), 4-(5′-subtituted 2′-phenyl-1H-indol-3′-yl)-6-aryl-1,4-dihydropyrano[2,3-c]pyrazol-3-amines (6a–i) and 5-(5′-substituted 2′-phenyl-1H-indol-3′-yl)-7-aryl-3H-pyrano[2,3-d]pyrimidin-4(5H)-ones (7a–i). Antibacterial activity results revealed that, compound 6a showed promising activity versus Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. Compound 6d exhibited good activity against S. aureus, K. pneumoniae and Pseudomonas aeruginosa. Antifungal activity results indicated that, compound 4d exhibited maximum zone of inhibition against Aspergillus oryzae and Aspergillus flavus. In case of antioxidant activity, compound 4a showed promising radical scavenging activity, ferric ions (Fe³⁺) reducing antioxidant power (FRAP) and metal chelating activity.     

Concise syntheses and HCV NS5B polymerase inhibition of (2′R)-3 and (2′S)-2′-ethynyluridine-10 and related nucleosides

(2′R)-Ethynyl uridine 3, and its (2′S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5′-O-triphosphates. Subsequently, this lead to the discovery of the 2′-β-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.     

John Montgomery's legacy: carbocyclic adenosine analogues as SAH hydrolase inhibitors with broad-spectrum antiviral activity

Ever since the S-adenosylhomocysteine (AdoHcy, SAH) hydrolase was recognized as a pharmacological target for antiviral agents (J. A. Montgomery et al., J. Med. Chem. 25:626-629, 1982), an increasing number of adenosine, acyclic adenosine, and carbocyclic adenosine analogues have been described as potent SAH hydrolase inhibitors endowed with broad-spectrum antiviral activity. The antiviral activity spectrum of the SAH hydrolase inhibitors include pox-, rhabdo-, filo-, arena-, paramyxo-, reo-, and retroviruses. Among the most potent SAH hydrolase inhibitors and antiviral agents rank carbocyclic 3-deazaadenosine (C-c3 Ado), neplanocin A, 3-deazaneplanocin A, the 5'-nor derivatives of carbocyclic adenosine (C-Ado, aristeromycin), and the 2-halo (i.e., 2-fluoro) and 6'-R-alkyl (i.e., 6'-R-methyl) derivatives of neplanocin A. These compounds are particularly active against poxviruses (i.e., vaccinia virus), and rhabdoviruses (i.e., vesicular stomatitis virus). The in vivo efficacy of C-c3 Ado and 3-deazaneplanocin A has been established in mouse models for vaccinia virus, vesicular stomatitis virus, and Ebola virus. SAH hydrolase inhibitors such as C-c3Ado and 3-deazaneplanocin A should in thefirst place be considered for therapeutic (or prophylactic) use against poxvirus infections, including smallpox, and hemorrhagic fever virus infections such as Ebola.     

Synthesis of purine and pyrimidine 2′-deoxynucleosides from a 1,2-dithio sugar precursor

9-(2-S-Ethyl-2-thio- and α-D-mannofuranosyl)adenine (8α and 8β) were synthesized from ethyl 3,5,6-tri-O-acetyl-2-S-ethyl-1,2-dithio-α-D-mannofuranoside (1) by bromination followed by coupling of the resultant bromide (2) with 6-benzamido-(chloromercuri)purine. The 2-chloro analogues (10α and 10β) of 8α and 8β were obtained by way of a fusion reaction between 1,3,5,6-tetra-O-acetyl-2-S- ethyl-2-thio-α-D-mannofuranose (5) and 2,6-dichloropurine. Fusion of the bromide 2 with 2,4-bis(trimethylsilyloxy)pyrimidine and its 5-methyl derivative led to 1-(2-S- ethyl-2-thio-β-D-mannofuranosyl)uracil (16) and its thymine analogue (15). The action of Raney nickel led to rapid dechlorination of 10α and 10β, and all of the 2′-thio-nucleosides underwent desulfurization to give the corresponding 2′-deoxynucleosides. Sequential periodate oxidation-borohydride reduction converted the hexofuranosyl nucleosides into their pentofuranosyl analogues. Thus prepared were 9-(2-deoxy-α-and β-D-arabino-hexofuranosyl)adenine (11α and 11β) and their 2-deoxy-D-threo-pentofuranosyl counterparts (6α and 2′-deoxy-3′-epiadenosine, 6β), and 1-(2-deoxy- β-D-arabino-hexofuranosyl)-thymine (17) and -uracil (18) and their 2-deoxy-D-threo-pentofuranosyl counterparts (3′-epithymidine, 21, and 2′-deoxy-3′-epiuridine, 20). Detailed n.m.r.-spectral correlations are described for the series, and various derivatives of the nucleosides are reported.     

New metabolites from the alga-derived fungi Penicillium thomii Maire and Penicillium lividum Westling

A new meroterpenoid, austalide H acid ethyl ester (1), 5-(2′,4′-dihydroxy-6′-methylphenyl)-3-methylfuran-2-carboxylic acid (2), 5-(2′-hydroxy-6′-methylphenyl)-3-methylfuran-2-carboxylic acid (3) and 5-((6′-methyl-4′-oxo-3′,4′-dihydro-2H-pyran-2′-yl)methyl)-3-methylfuran-2-carboxylic acid (4), along with six known compounds, austalides H, J, K, and P (5–8), questin (9) and sulochrin (10) were isolated from the lipophilic extract of the alga-derived fungi Penicillium thomii KMM 4645 and Penicillium lividum KMM 4663. The structures of the isolated compounds were determined based on spectroscopic methods. The austalides showed significant inhibitory activity against endo-1,3-β-d-Glucanase from a crystalline stalk of the marine mollusk Pseudocardium sachalinensis.     

Ehrenasterol and biemnic acid; new bioactive compounds from the Red Sea sponge Biemna ehrenbergi

In continuation of our efforts to identify bioactive compounds from the Red Sea marine sponges, we have recently investigated the organic extract of the sponge Biemna ehrenbergi. This study resulted in the isolation of eight compounds including a new sterol, ehrenasterol (1), a new C₂₄-acetylenic acid, biemnic acid (2), together with six known compounds including a hopanoid, three steroids and two nucleosides. The isolated compounds were identified as (22E)-ergosta-22-ene-8,14-epoxy-3,7-dione (1), (E)-tetracos-8-en-5-ynoic acid (2), (22E)-ergosta-5,8,22-trien-7-one-3β-ol (3), 32,35-anhydrobacteriohopanetetrol (4), (24R)-ergosta-6,22-diene-5,8-epidioxy-3-ol (5), melithasterol B (6), thymidine (7) and 2′-deoxyuridine (8). The structures of the isolated compounds were assigned by different spectral data including 1D and 2D NMR (COSY, HSQC, and HMBC) and high-resolution mass spectrometry. Compound 1 displayed inhibition zone of 20 mm at 100 μg/disc against Escherichia coli in the disc diffusion assay. Similarly, compounds 2 and 4 displayed inhibition zones of 20 and 18 mm respectively against Candida albicans at the same concentration. Compounds 1–3 displayed weak cytotoxic activity against human colon adenocarcinoma (HCT-116) cancer cell line.     

6′-Fluoro-3-deazaneplanocin: Synthesis and antiviral properties,including Ebola

A convenient stereospecific synthesis of 6′-fluoro-3-deazaneplanocin (6) has been accomplished from d-ribose in 15 steps. It is reported to possess significant activity towards Ebola (Zaire, Vero, μM: EC₅₀?<?0.36; CC₅₀ 125; SI?>?347) with moderate inhibition of the target enzyme (S-adenosylhomocysteine hydrolase), which did not correlate directly with its anti-Ebola effects. Compound 6, with limited cytotoxicity, also displayed activity against measles, H1N1 and Pichinde.     

Investigation of C-5 alkynyl (alkynyloxy or hydroxymethyl) and/or N-3 propynyl substituted pyrimidine nucleoside analogs as a new class of antimicrobial agents

The resurgence of mycobacterial infections and the emergence of drug-resistant strains urgently require a new class of agents that are distinct than current therapies. A group of 5-ethynyl (6–10), 5-(2-propynyloxy) (16, 18, 20, 22, 24), 5-(2-propynyloxy)-3-N-(2-propynyl) (17, 19, 21, 23, 25) and 5-hydroxymethyl-3-N-(2-propynyl) (30–33) derivatives of pyrimidine nucleosides were synthesized and evaluated against mycobacteria [Mycobacterium tuberculosis (Mtb), Mycobacterium bovis (BCG) and Mycobacterium avium], gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and gram-negative bacteria (Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa) alone and in combination with existing drugs in in vitro assays. Although several compounds exhibited marked inhibitory activity at a higher concentration against Mtb, M. bovis, S. aureus and E. faecalis, they displayed unexpected synergistic and additive interactions at their lower concentrations with antitubercular drugs isoniazid and rifampicin, and antibacterial drug gentamicin. The active analogues were also found to inhibit intracellular Mtb in a human monocytic cell line infected with H37Ra. Oral administration of 5-hydroxymethyl-3-N-(2-propynyl)-3′-azido-2′,3′-dideoxyuridine (32) and 5-hydroxymethyl-3-N-(2-propynyl)-2′,3′-dideoxyuridine (33) at a dose of 100 mg/kg for two weeks showed promising in vivo effects in mice infected with Mtb (H37Ra). No in vitro cytotoxicity of the test compounds was observed up to the highest concentration tested (CC50 > 300 μg/mL).     

Synthesis and anti-HIV activity of 2′-deoxy-2′-fluoro-4′-C-ethynyl nucleoside analogs

Based on the favorable antiviral profiles of 4′-substituted nucleosides, novel 1-(2′-deoxy-2′-fluoro-4′-C-ethynyl-β-d-arabinofuranosyl)-uracil (1a), -thymine (1b), and -cytosine (2) analogs were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC₅₀ values of 86 and 1.34 nM, respectively, without significant cytotoxicity. Compound 2 was 35-fold more potent than AZT against wild-type virus, and also retained nanomolar antiviral activity against resistant strains, NL4-3 (K101E) and RTMDR. Thus, 2 merits further development as a novel NRTI drug.     

Lignan glycosides from the Rhizomes of Smilax trinervula and their Biological activities

Phytochemical investigation of the rhizomes of Smilax trinervula led to isolation and structure elucidation of eight lignan glycosides, including five new lignans, namely, (7S, 8R, 8′R)-4, 4′, 9-trihydroxy-3, 3′, 5, 5′-tetramethoxy-7, 9′-epoxylignan-7′-one 4′-O-β-d-glucopyranoside (1), (7S, 8R, 8′R)-4, 4′, 9-trihydroxy-3, 3′, 5, 5′-tetramethoxy-7, 9′-epoxylignan-7′-one 4-O-β-d- glucopyranoside (2) (7S, 8R)-4, 9, 9′-trihydroxy-3, 3′, 5-trimethoxy-4′, 7-epoxy-8, 5′-neolignan 9′-O-β-d-glucopyranoside (3), (7R, 8R)-4, 9, 9′-trihydroxy-3, 5-dimethoxy-7.O.4′, 8.O.3′- neolignan 9′-O-β-d-glucopyranoside (4), and (7S, 8R)-4, 9, 9′-trihydroxy-3, 3′, 5-trimethoxy-8, 4′-oxy-neolignan 4-O-β-d-glucopyranoside (5), along with three known compounds (6-8). Their structures were established mainly on the basis of 1D and 2D NMR spectral data, ESI–MS and comparison with the literature. Compounds 1-8 were tested in vitro for their cytotoxic activity against four human tumor cell lines (SH-SY5Y, SGC-7901, HCT-116, Lovo). Compounds 3 and 5 exhibited cytotoxic activity against Lovo cells, with IC₅₀ value of 10.4 μM and 8.5 μM, respectively.     

Chemical constituents from Oncocalyx glabratus and their biological activities

Chemical investigation of the aerial parts of Oncocalyx glabratus resulted in the isolation of three new flavan derivatives, 5,3′,4′-trihydroxyflavan 7-O-gallate (1), 5,4′-dihydroxyflavan 7-3′-O-digallate (2) and 5,3′-dihydroxyflavan 7-4′-O-digallate (3), named oncoglabrinol A, B and C, respectively, together with four known flavonols, (+)-catechin (4), (+)-catechin-7-O-gallate (5), catechin-7-4′-O-digallate (6A) and catechin-7-3′-O-digallate (6B). The structures of the compounds were established by 1D, 2D NMR and ESI-HRMS spectral analyses. The biological activity of the compounds was tested through a series of in vitro assays designed for determining cytotoxicity, antiviral activity against hepatitis B virus, and antidiabetic activity. All compounds were found non-toxic and showed moderate anti-HBV activity. Compounds 3 and 6 showed dual PPAR agonistic activity while others were not effective.     

Triethylated chromones with substituted naphthalenes as tubulin inhibitors

Previously synthesized 2-(benzo[b]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (1, TEDB-TB) and 2-(naphth-1′-yl)-6,8,8-triethyldesmosdumotin B (2) showed potent activity against multiple human tumor cell lines, including a multidrug-resistant (MDR) subline, by targeting spindle formation and/or the microtubule network. Consequently, ester analogues of hydroxylated naphthyl substituted TEBDs (3–5) were prepared and evaluated for their effects on tumor cell proliferation and on tubulin assembly. Among all new compounds, compound 6, a 4′-acetoxynaphthalen-1′-yl derivative, displayed the most potent antiproliferative activity (IC₅₀ 0.2–5.7 μM). Selected analogues were confirmed to be tubulin assembly inhibitors in cell-free and cell-based assays using MDR tumor cells. The new analogues partially inhibited colchicine binding to tubulin, suggesting their binding mode would be different from that of colchicine. This observation was supported by computational docking model analyses. Thus, the newly synthesized triethylated chromones with esterified naphthalene groups have good potential for development as a new class of mitotic inhibitors that target tubulin.     

Minor phenolics from Angelica keiskei and their proliferative effects on Hep3B cells

A new coumarin, (?)-cis-(3′R,4′R)-4′-O-angeloylkhellactone-3′-O-β-d-glucopyranoside (1) and two new chalcones, 3′-[(2E)-5-carboxy-3-methyl-2-pentenyl]-4,2′,4′-trihydroxychalcone (4) and (±)-4,2′,4′-trihydroxy-3′-{2-hydroxy-2-[tetrahydro-2-methyl-5-(1-methylethenyl)-2-furanyl]ethyl}chalcone (5) were isolated from the aerial parts of Angelica keiskei (Umbelliferae), together with six known compounds: (R)-O-isobutyroyllomatin (2), 3′-O-methylvaginol (3), (?)-jejuchalcone F (6), isoliquiritigenin (7), davidigenin (8), and (±)-liquiritigenin (9). The structures of the new compounds were determined by interpretation of their spectroscopic data including 1D and 2D NMR data. All known compounds (2, 3, and 6–9) were isolated as constituents of A. keiskei for the first time. To identify novel hepatocyte proliferation inducer for liver regeneration, 1–9 were evaluated for their cell proliferative effects using a Hep3B human hepatoma cell line. All isolates exhibited cell proliferative effects compared to untreated control (DMSO). Cytoprotective effects against oxidative stress induced by glucose oxidase were also examined on Hep3B cells and mouse fibroblast NIH3T3 cells and all compounds showed significant dose-dependent protection against oxidative stress.     

Benzophenones and xanthones from Garcinia cantleyana var. cantleyana and their inhibitory activities on human low-density lipoprotein oxidation and platelet aggregation

Three benzophenones, 2,6,3′,5′-tetrahydroxybenzophenone (1), 3,4,5,3′,5′-pentahydroxybenzophenone (3) and 3,5,3′,5′-tetrahydroxy-4-methoxybenzophenone (4), as well as a xanthone, 1,3,6-trihydroxy-5-methoxy-7-(3′-methyl-2′-oxo-but-3′-enyl)xanthone (9), were isolated from the twigs of Garcinia cantleyana var. cantleyana. Eight known compounds, 3,4,5,3′-tetrahydroxy benzophenone (2), 1,3,5-trihydroxyxanthone (5), 1,3,8-trihydroxyxanthone (6), 2,4,7-trihydroxyxanthone (7), 1,3,5,7-tetrahydroxyxanthone (8), quercetin, glutin-5-en-3β-ol and friedelin were also isolated. The structures of the compounds were elucidated by spectroscopic methods. The compounds were investigated for their ability to inhibit low-density lipoprotein (LDL) oxidation and platelet aggregation in human whole blood in vitro. Most of the compounds showed strong antioxidant activity with compound 8 showing the highest inhibition with an IC₅₀ value of 0.5 μM, comparable to that of probucol. Among the compounds tested, only compound 4 exhibited strong inhibitory activity against platelet aggregation induced by arachidonic acid (AA), adenosine diphosphate (ADP) and collagen. Compounds 3, 5 and 8 showed selective inhibitory activity on platelet aggregation induced by ADP.     

Synthesis and Anticancer Activity of 3-(3-Oxoprop-1-enyl)-Substituted Analogues of Carbocyclic Pyrimidine Nucleosides and 2′,3′-Dideoxy Pyrimidine Nucleosides

Abstract

Various 2′, 3′ -dideoxy and carbocyclic pyrimidine nucleosides, and their corresponding 3-(3-oxoprop-1-enyl) derivatives, have been synthesized and evaluated against murine L1210 and P388 leukemias and Sarcoma 180 and human CCRF-CEM lymphoblastic leukemia. Among the compounds tested, 3-(3-oxoprop-1-enyl)-3′ -fluoro-3′ -deoxythymidine (17), 3-(3-oxoprop-1-enyl)-3′ -azido-3′ -deoxythymidine (15) and 3-(3-oxoprop-1-eny!)-(+)-1-[(lα, 3β, 4α)-3-hydroxy-4-(hydroxymethyl)cyclopentyl]-5-methyl-2,4 (lH,3H)pyrimidinedione (6) were found to be the most active with ED₅₀, values of 0.5,0.2,0.1, and 0.3 μM; 1.2, 0.5,1.0 and 1.0 μM; and 0.8,0.7,1.5, and 3.0μM, respectively. Our preliminary findings indicate that the 3-(3-oxoprop-1-enyl) derivative of carbocyclic thymidine is approximately 7 times more active than the 3-(3-oxoprop-1-enyl) derivative of carbocyclic thymine riboside against L1210 leukemia cells in vitro, with ED₅₀ values of 0.8 μM and 5.5 μM, respectively. These findings suggest that the cytotoxicity of these compounds not only is dependent upon the 3-(3-oxoprop-1-enyl)-substituted group, but also may vary with the sugar moiety.     

2′-Azido-2′-deoxy- and 2′-amino-2′-deoxy-β-d-arabino-furanosyl purine nucleosides

A general method for the preparation of 2′-azido-2′-deoxy- and 2′-amino-2′-deoxyarabinofuranosyl-adenine and -guanine nucleosides is described. Selective benzoylation of 3-azido-3-deoxy-1,2-O-isopropylidene-α-d-glucofuranose afforded 3-azido-6-O-benzoyl-3-deoxy-1,2-O-isopropylidene-α-d-glucofuranose (1). Acid hydrolysis of 1, followed by oxidation with sodium metaperiodate and hydrolysis by sodium hydrogencarbonate gave 2-azido-2-deoxy-5-O-benzoyl-d-arabinofuranose (3), which was acetylated to give 1,3-di-O-acetyl-2-azido-5-O-benzoyl-2-deoxy-d-arabinofuranose (4). Compound 4 was converted into the 1-chlorides 5 and 6, which were condensed with silylated derivatives of 6-chloropurine and 2-acetamido-hypoxanthine. The condensation reaction gave α and β anomers of both 7- and 9-substituted purine nucleosides. The structures of the nucleosides were determined by n.m.r. and u.v. spectroscopy, and by correlation of the c.d. spectra of the newly prepared nucleosides with those published for known purine nucleosides.