ACYCLIC NUCLEOSIDE/NUCLEOTIDE ANALOGUES WITH AN IMIDAZOLE RING SKELETON

Syntheses of a few acyclic nucleoside and acyclic nucleoside phosphonate analogues containing an imidazole ring have been reported. These analogues include methyl 1-(2-hydroxyethoxymethyl)imidazole-4,5-dicarbo-xylate (1), 4,5-dicarbamoyl-1-(2-hydroxyethoxymethyl)imidazole (2), 4,5-dicya-no-1-(2-hydroxyethoxymethyl)imidazole (4), Methyl 1-(2-bromoethoxymethyl)- imidazole-4,5-dicarboxylate (7), 4,5-dicyano-(2-bromoethoxymethyl)imidazole (8), and Methyl 1-(2-phosphonomethoxyethyl)imidazole (10). Also reported are a few potential prodrugs of the above compounds, including the acetyl derivatives 5 and 6 (of 1 and 4, respectively), and the diethyl phosphonate ester 9 (of 10). In addition, the corresponding benzyl-protected precursors 11 and 12 (of 1 and 4, respectively), along with their common hydrolysis product, 1-(2-benzyloxy-ethoxymethyl)-4,5-imidazoledicarboxylic acid (3), are reported. Another potential prodrug included in the list is 1-(2-acetoxyethyl)-4,5-dicyanoimidazole (15). The compounds were screened for in vitro antiviral activity against a wide variety of herpes and respiratory viruses. The most active compound was the phosphonate analogue 9 which exhibited an anti-measles virus activity with an EC₅₀ of <2.5 μg/mL and an SI value of > 176.     

Synthesis of 3-Aminoimidazo[4,5-c]pyrazole Nucleoside via the N-N Bond Formation Strategy as a [5:5] Fused Analog of Adenosine

3-Amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole (2) was synthesized via an N-N bond formation strategy by a mononuclear heterocyclic rearrangement (MHR). A series of 5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl-4-(1,2,4-oxadiazol-3-yl)imidaz-oles (6a-d), with different substituents at the 5-position of the 1,2,4-oxadiazole, were synthesized from 5-amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamide (AICA Ribose, 3). It was found that 5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)imidazole (6a) underwent the MHR with sodium hydride in DMF or DMSO to afford the corresponding 3-acetamidoimidazo[4,5-c]pyrazole nucleoside(s) (7b and/or 7a) in good yields. A direct removal of the acetyl group from 3-acetamidoimidazo[4,5-c]pyrazoles under numerous conditions was unsuccessful. Subsequent protecting group manipulations afforded the desired 3-amino-6-(β-D-ribofuranosyl)imidazo[4,5-c]pyrazole (2) as a 5:5 fused analog of adenosine (1).     

8-Aza-1-deazapurine Nucleosides as Antiviral Agents

Abstract

2′,3′-Dideoxy-8-aza-1-deazaadenosine (21) and its α-anomer (20) were synthesized via glycosylation of 7-chloro-3H-1,2,3-triazolo[4,5-b]pyridi-ne with 2,3-dideoxy-5-O-[(1, 1)-dimethylethyl)diphenylsilyl]-D-glycero-o-pen-tofuranosyl chloride. The reaction gave a mixture of α- and β-anomers of N³-, N⁴- and N¹-glycosylated regioisorners (12–15). The α- and β-anomers of the N⁴-glycosylated isomer 26 and 27 were also synthesized through the glycosylation of 8-aza-1-deazaadenine with 1-acetoxy-2,3-dideoxy-5-O-f(1,1-di-methylethyl)dimethylsilyl]-D-glycero-pentouranose. These dideoxynucleo-sides and a series of previously synthesized 8-aza-1-deazapurine nucleosidcs were tested for activity against several DNA and RNA viruses, HIV-1 included. The α- and β-anomers of 7-chloro-3-(2-deoxy-D-erythro-pentofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (3a and 4) showed activities against Sb-1 and Coxs viruses. The α- and β-anomers of 2′,3′-dideoxy-8-aza-1-deazaadenosine (20 and 21) were found active as inhibitors of adenosine deaminase.     

Synthesis,antiviral activity and structure–activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization

Novel 1-(1-aryl-4,5dihydro-1H-imidazoline)-3-chlorosulfonylourea derivatives 3a–3f were synthesized in the reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with chlorosulfonyl isocyanate. The second series of compounds 4a–4f was prepared from the respective 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorsulfonylureas 3a–3f and 1,1′-carbonyldiimidazole (CDI). The selected compounds were tested for their activity against Herpes simplex virus and coxsackievirus B3 (CVB3). It was determined that three derivatives, i.e 3d, 4a and 4d are active against Herpes simplex virus (HSV-1). Compounds 3d and 4c are active against CVB3. Their favorable activity can be primarily attributed to their low lipophilicity values. Moreover, the lack of substituent in the phenyl moiety or 4-methoxy substitution can be considered as the most beneficial for the antiviral activity.     

Synthesis and Biological Evaluation of Some D-Arabino- and D-Lyxofuranosyl-Pyridine C-Nucleosides

Abstract

The addition reaction of either 3-bromo-5-lithiopyridine (2a) or 3-cyano-5-lithiopyridine (2b) to 2,3:4,5-di-O-isopropylidene-aldehydo-D-arabinose (1) or 2,4:3,5-di-O-benzylidene-aldehydo-D-lyxose (8) gave respectively a D-gluco/D-manno mixture of 3-bromo- and 3-cyano-5-(2,3:4,5-di-O-isopropylidene-pentitol-1-yl)pyridine (3a,b) or a D-galacto/D-talo mixture of respectively 3-bromo- and 3-cyano-5-(2,4:3,5-di-O-benzylidene-pentitol-1-yl)pyridine (9a,b). Mesylation of C-1′ followed by reaction with CF₃COOH/H₂O resulted in the formation of the corresponding D-arabino- or D-lyxofuranosyl pyridine C-nucleosides. The cyano group of (5b) and (11b) was converted into a carbamoyl group using Amberlite IRA 400 (OH^?). 3-Cyano-5-D-arabinofuianosylpyridine (5b) was converted into 3-thiocarbamoyl-5-D-arabinofuranosyl-pyridine (7) using H₂S and triethylamine.

None of the test compounds showed a marked cytostatic or antiviral activity in vitro.     

New Acyclic Quinoxaline Nucleosides. Synthesis and Anti-Hiv Activity

A series of acyclonucleosides substituted 1-(4,5-dihydroxypentyl) (13-8) and 2-(4,5-dihydroxypentyloxy)quinoxalines (19-24) were synthesized by the sharpless asymmetric dihydroxylation of the derivatives 1-6 and 7-12, respectively. Treatment of the quinoxaline base 26 with (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-p-toluenesulfonate (27) in the presence of NaH/DMF furnished 28. Acid hydrolysis of 28 gave 1-(2,3-dihydroxypropyl)-6,7-dimethyl-quinoxaline-2-one (29). Alternatively, 29 was prepared by sharpless dihydroxylation of 30. All the compounds were evaluated for their in vitro anti-HIV-1 and HIV-2 in MT-4 cell and found inactive, except 29, which showed inhibition of HIV-1 with EC₅₀ value of 0.15 ± 0.1 μg/ml and a therapeutic index (SI) of 73.     

Asymmetric Hydrolysis of Prochiral Diesters with Pig Liver Esterase. Preparation of Optically Active Intermediates for the Synthesis of (+)-Biotin and (+)-α-Methyl-3,4-dihydroxyphenylalanine

With pig liver esterase, 1,3-dibenzyl-4,5-cis-bis(alkyloxycarbonyl)-2-oxoimidazolidine (1) was asymmetrically hydrolyzed to (4S,5R)-1,3-dibenzyl-5-alkyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (2). This acid 2 was reduced with lithium borohydride to (4S,5R)-1,3-dibenzyl-5-hydroxymethyl-2-oxoimidazolidine-4-carboxylic acid lactone (3), which is known to be converted to (+)-biotin (4). With the same esterase, diethyl 3,4-dimethoxyphenylmethyl-(methyl)malonate (5) was asymmetrically hydrolyzed to (R)-ethyl hydrogen 3,4-dimethoxy-phenylmethyl(methyl)malonate (6), which can be converted to (S)-α-methyl-3,4-dihydroxyphenyl-alanine(l-α-methyldopa) (9).     

Synthesis and Biological Activity of 4-Amino-1-(β-D-ribofuranosyl)imidazo[4,5-d]pyridazin-7-one

Abstract

The Lewis acid catalyzed ribosylation of 5(4)-cyano-4(5)-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-imidazole (2) with 1-O-acetyl-2,3,5-tri-O-benzoyl-B-D-ribose gave only 4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzoy 1-B-D-ribofuranosyl)imidazole-5-carbonitrile (3). Treatment of 3 with methanolic ammonia gave 4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(6-D-ribofuranosyl)imidazole-5-carbonitrile (4). Treatment of 4 with hydrogen peroxide in ammonia gave -(5-methyl-1,2,4-oxadiazol-3-yl)-1-(B-D-ribofuranosyl)imidazole-5-carboxamide (5). When 5 was treated with sodium hydride in dimthyl-sulfoxide a rearrangement (mononuclear heterocyclic rearrangement, m.h.r.) occurred to give a modest 17% yield of 4-acetamido-1-(B-D ribofuranosyl)imidazo[4,5-d]pyridazin-7-one (6). Treatment of 6 with aqueous ammonia gave4-amino-l-(B-D-ribofuranosyl)imidazo[4,5-d]pyridazin-7-one (1). The synthesis of compound 1 using the m.h.r. for the preparation of a single regioisomer of the imidazo[4,5-d]pyridazin-7-one ring system, has demonstrated the potential of this methodology. Neither compound 5 nor 6 affected the growth or replication of human foreskin fibroblasts (HFF cells) or human cytomegalovirus (HCMV). In contrast, compound 1 inhibited the replication of HCMV (IC₅₀=29 μM) but produced visual cytotoxicity in uninfected HFF cells (IC₅₀=70μM). Compound 1 also inhibited the proliferation of L1210 murine leukemic cells (IC₅₀=25μM), whereas the precursors 4 and 6 did not.     

Novel 4,5-dihydro-thiazinogeldanamycin in a gdmP mutant strain of Streptomyces hygroscopicus 17997

Novel geldanamycin derivative, 4,5-dihydro-thiazinogeldanamycin (3), was characterized from the gdmP mutant in Streptomyces hygroscopicus 17997, besides expected 4,5-dihydro-geldanamycin (2). The presence of this compound would suggest an unknown post-PKS modification in geldanamycin biosynthesis. Compound 3 exhibited moderate anti-HSV-1-virus activity and higher water solubility than geldanamycin (1). Cysteine served as a precursor to synthesize 3, whose formation required obligatory enzymatic assistance.     

Desferrithiocin analogue iron chelators: iron clearing efficiency,tissue distribution,and renal toxicity

The current solution to iron-mediated damage in transfusional iron overload disorders is decorporation of excess unmanaged metal, chelation therapy. The clinical development of the tridentate chelator deferitrin (1, Table 1) was halted due to nephrotoxicity. It was then shown by replacing the 4′-(HO) of 1 with a 3,6,9-trioxadecyloxy group, the nephrotoxicity could be ameliorated. Further structure–activity relationship studies have established that the length and the position of the polyether backbone controlled: (1) the ligand’s iron clearing efficiency (ICE), (2) chelator tissue distribution, (3) biliary ferrokinetics, and (4) tissue iron reduction. The current investigation compares the ICE and tissue distribution of a series of (S)-4,5-dihydro-2-[2-hydroxy-4-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 3–5) and the (S)-4,5-dihydro-2-[2-hydroxy-3-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table 1, 8–10). The three most effective polyether analogues, in terms of performance ratio (PR), defined as mean ICE_primate/ICE_rodent, are 3 (PR 1.1), 8, (PR 1.5), and 9, now in human trials, (PR 2.2). At the onset of the clinical trial on 9, no data were available for ligand 3 or 8. This is unfortunate, as 3 has many advantages over 9, e.g., the ICE of 3 in rats is 2.5-fold greater than that of 9 and analogue 3 achieves very high levels in the liver, pancreas, and heart, the organs most affected by iron overload. Finally, the impact of 3 on the urinary excretion of kidney injury molecule-1 (Kim-1), an early diagnostic biomarker for monitoring acute kidney toxicity, has been carried out in rats; no evidence of nephrotoxicity was found. Overall, the results suggest that 3 would be a far superior clinical candidate to 9.     

Nucleosides. II. Synthesis and Properties of 3,4-Diaryl-4,5-dihydro-1-(β-D-ribofuranosyl)-1,2,4-triazole-5-thiones

Abstract

3,4-Diaryl-4,5-dihydro-1,2,4-triazole-5-thiones (1a-c) were silylated to give compounds (2a-c) which were condensed with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (3) in the presence of trimethylsilyl trifluoromethane sulfonate to afford the corresponding nucleosides 4a-c. Treatment of 4a-c with sodium methoxide in methanol at room temperature afforded the debenzoylated nucleosides 5a-c. The reaction of 5a with acetone in the presence of p-toluenesulfonic acid gave the 2′, 3′-isopropylidene derivative (6a). Phosphorylation of 6a with phosphoryl chloride and triethylphosphate followed by treatment with barium hydroxide afforded barium 3,4-diphenyl-4,5-dihydro(β-D-ribofuranosyl)-1,2,4-triazole-5-thione-5′- monophosphate, which gave after lyophilization the free acid (7a)     

Design,synthesis and antiviral evaluation of novel acyclic phosphonate nucleotide analogs with triazolo[4,5-b]pyridine,imidazo[4,5-b]pyridine and imidazo[4,5-b]pyridin-2(3H)-one systems

Abstract

A new series of phosphonylated triazolo[4,5-b]pyridine (1-deaza-8-azapurine), imidazo[4,5-b]pyridine (1-deazapurine) and imidazo[4,5-b]pyridin-2(3H)-one (1-deazapurin-8-one) were synthesized from 2-chloro-3-nitropyridine and selected diethyl ?-aminoalkylphosphonates followed by reduction of the nitro group and cyclization. In the final step O,O-diethylphosphonates were transformed into the corresponding phosphonic acids. All synthesized compounds were evaluated in vitro for inhibitory activity against a broad variety of DNA and RNA viruses and their cytotoxic potencies were also established. Compound 12f showed marginal activity against cytomegalovirus Davis strain (EC₅₀?=?76.47?μM) in human embryonic lung (HEL) cells while compounds 10g (EC₅₀?=?52.53?μM) and 12l (EC₅₀?=?61.70?μM) were minimally active against the varicella-zoster virus Oka strain in HEL cells. Compounds under investigation were not cytotoxic at the maximum concentration evaluated (100?µM).     

8-Aza Analogues of Deaza Purine Nucleosides. Synthesis and Biological Evaluation of 8-Aza-1-deazaadenosine and 2′-Deoxy-8-aza-1-deazaadenosine

Abstract

The syntheses of 7-amino-3-(β-D-ribofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (8-aza-1-deazaadenosine) (2) and 7-amino-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (2′-deoxy-8-aza-1-deazaadenosine) (3) by glycosylation of the anion of 7-chloro-3H-1,2,3-triazolo[4,5-b]pyridine are described. The anomeric configuration as well as the position of glycosylation were determined by ¹H, ¹³ NMR, UV and N.O.E. difference spectroscopy. The cytotoxicity of these nucleosides against several murine and human tumor cell lines is discussed. Compounds 2 and 3 proved to be good inhibitors of adenosine deaminase.     

Analogues of Azepinomycin as Inhibitors of Guanase

Abstract

Synthesis and biochemical screening against guanase of analogues of the naturally occurring guanase inhibitor azepinomycin (2) are reported. Compound e-amino-5,6,7,8,-tetrahydro-4H-imidazo[4,5-e][1,4]diazepine-5,8-dione (3) was synthesized in six steps commencing with 1-benzyl-5-nitroimidazole-4-carboxylic acid (5). Compound 3 and its synthetic precursor 3-benzyl-6-(N-benzyloxycarbonyl)amino-5,6,7,8-tetrahydro-4H-imidazo[4,5-e][1,4]diazepine-5,8-dione (12) were screened against rabbit liver guanase. Both were found to be moderate inhibitors of the enzyme with K₁′s in the range of 10^?4 M.     

Synthesis of novel selenium containing sulfa drugs and their antibacterial activities

Synthesis of 3-[4-(N-substituted sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyri-do[3′,2′:4,5]selenolo[3,2-d]pyrimidines,7-[4-(N-substituted sulfamoyl)phenyl]-7,8-dihydro-8-oxo-3,4-diphenylpyrimido[4′,5′:4,5]selenolo [2,3-c]pyridazines and 1-[4-(N-substituted sulfamoyl)phenyl]-1,11-dihydro 11-oxo-4-methylpyrimido[4′,5′:4,5]selenolo[2,3-b]quinolines is reported. 4-Amino-N-pyrimidine-2-ylbenzene sulfonamide (a), 4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzene sulfonamide (b), N-[(4-aminophenyl)sulfonyl] acetamide (c) with N-ethoxymethyleneamino of selenolo pyridine, selenolo pyridazine and selenolo quinoline derivatives respectively were obtained starting from 1-amino-N ⁴-substituted sulfanilamides. Spectroscopic data (IR, ¹H NMR, ¹³C NMR and Mass spectral) confirmed the structure of the newly synthesized compounds. Substituted pyrimidines, pyridazines and quinolines were screened for antibacterial activity against gram-positive and gram-negative bacteria. Selenolo derivative of N-[(4-aminophenyl)sulfonyl] acetamide (substitutent of sulfacetamide c) showed strong bactericidal effect against all the tested organisms. Selenolo[3,2-d]pyrimidin (substitutent a) showed a good bactericidal effect against Serratia marcescens, Staphylococcus aureus and Escherichia coli. Compounds selenolo[2,3-c]pyridazine (substitutent b), selenolo[2,3-b]quinoline(substitutents c)) exhibited a moderate bactericidal effect against Serratia marcescens. None of the synthesized seleno pyridazines has a considerable antimicrobial activity against the tested organisms. The minimum inhibitory concentration (MIC) of the most active compound-3-[4-(N-acetyl sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyrido[3′,2′:4,5]selenolo [3,2-d]pyrimidine was 10 mg ml⁻¹.     

Biotransformation of gallic acid by <Emphasis Type="Italic">Beauveria sulfurescens</Emphasis> ATCC 7159

Preparative-scale fermentation of gallic acid (3,4,5-trihydroxybenzoic acid) (1) with Beauveria sulfurescens ATCC 7159 gave two new glucosidated compounds, 4-(3,4-dihydroxy-6-hydroxymethyl-5-methoxy-tetrahydro-pyran-2-yloxy)-3-hydroxy-5-methoxy-benzoic acid (4), 3-hydroxy-4,5-dimethoxy-benzoic acid 3,4-dihydroxy-6-hydroxymethyl-5-methoxy-tetrahydro-pyran-2-yl ester (7), along with four known compounds, 3-O-methylgallic acid (2), 4-O-methylgallic acid (3), 3,4-O-dimethylgallic acid (5), and 3,5-O-dimethylgallic acid (6). The new metabolite genistein 7-O-β-D-4″-O-methyl-glucopyranoside (8) was also obtained as a byproduct due to the use of soybean meal in the fermentation medium. The structural elucidation of the metabolites was based primarily on 1D-, 2D-NMR, and HRFABMS analyses. Among these compounds, 2, 3, and 5 are metabolites of gallic acid in mammals. This result demonstrated that microbial culture parallels mammalian metabolism; therefore, B. sulfurescens might be a useful tool for generating mammalian metabolites of related analogs of gallic acid (1) for complete structural identification and for further use in investigating pharmacological and toxicological properties in this series of compounds. In addition, a GRE (glucocorticoid response element)-mediated luciferase reporter gene assay was used to initially screen for the biological activity of the 6 compounds, 2–6 and 8, along with 1 and its chemical O-methylated derivatives 9–13. Among the 12 compounds tested, 11–13 were found to be significant, but less active than the reference compounds of methylprednisolone and dexamethasone.     

Steroidal Metabolites Transformed by <Emphasis Type="Italic">Marchantia polymorpha</Emphasis> Cultures Block Breast Cancer Estrogen Biosynthesis

Suspension of cultured cells of Marchantia polymorpha have the potential to hydrogenate the olefinic bonds present in androst-1,4-dien-3,17-dione (boldione, 1) to afford dihydroandrost-3,17-dione derivatives including: androst-4-ene-3,17-dione (androstenedione, 4-AD, 2), 5α-androstane-3,17-dione (androstenedione, AD, 4), and the less abundant metabolite 5α-androst-1-ene-3,17-dione (1-androstenedione, 1-AD, 3). After isolation and purification, these metabolites were characterized on the basis of spectroscopic analyses using 1D and 2D NMR as well as mass spectrometry. Cytotoxicity of the biotransformation products against breast adenocarcinoma cells (MCF-7) was assessed by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and cell death (apoptosis or necrosis) was assayed by acridine orange/ethidium bromide staining. Aromatase (cytochrome P450 19 enzyme, CYP19) inhibitory activity was measured by a tritiated water release assay and by direct measurement of bio-transformed steroids using the tritium labeled substrate ³H-androst-4-ene-3,17-dione. CYP19 mRNA expression in MCF-7 cells was analyzed by real-time PCR. Steroidal products 3 and 4 revealed a highly significant inhibition of MCF-7 cell growth that was predominantly due to apoptosis not necrosis. Steroidal products 3 and 4 are both potent inhibitors of aromatase activity and CYP19 mRNA expression, while 2 is a known substrate for aromatase. These data establish that metabolites 3 and 4 are potent chemical agents against breast cancer via aromatase inhibitory mechanism. Results were interpreted via virtual docking of the biotransformation products to the human placental aromatase active site.     

POTENT IN VITRO ANTICANCER ACTIVITIES OF RING-EXPANDED (“FAT”) NUCLEOSIDES CONTAINING THE IMIDAZO[4,5-E][1,3]DIAZEPINE RING SYSTEM

The ring-expanded (“fat”) nucleoside, 4,8-diamino-6-imino-6H-1-β-D-ribo- furanosylimidazo[4,5-e][1,3]diazepine (1) and its 2′,3′,5′-tri-O-benzoyl derivative (2) exhibited potent broad spectrum anticancer activities in vitro against a wide variety of human tumor cell lines. The tribenzoyl derivative 2 was found to be considerably more active than the parent nucleoside 1. Further studies using human prostate cancer cells PC-3 and DU-145 suggest that the treatment of exponentially growing culture cells with 1 and 2 leads to marked loss of cell viability in a dose-dependent manner.     

Stereoselective Reactions OF 1-(4,6-O-Benzylidene-2,3-Didehydro-2,3-dideoxy-3-nitro-β-D-hexopyranosyl)uracil with some Nucleophiles¶

Abstract

Michael addition of benzylamine, piperidine, morpholine, pyrrolidine, cyclohexylamine, allylamine and dimethylmalonate to the nitroolefin (5) generated in situ from 1-(4,6-O-benzylidene-3-deoxy-3-nitro-β-D-glucopyranosyl)uracil (4b) gave the corresponding 2-(substituted-amino)-3-deoxy-3-nitro-β-D-glucopyranosides (6a-f and 6h). Reaction of 4b with N,N-carbonyldiimidazole directly gave 6g. Compound 4b was converted into the 2-deoxy analogue (8), which was reduced to the 3-amino (9) and 3-hydroxylamino analogue (10).

     

Keto-fluorothiopyranosyl nucleosides: a convenient synthesis of 2- and 4-keto-3-fluoro-5-thioxylopyranosyl thymine analogs

A novel series of fluorinated keto-β-d-5-thioxylopyranonucleosides bearing thymine as the heterocyclic base have been designed and synthesized. Deprotection of 3-deoxy-3-fluoro-5-S-acetyl-5-thio-d-xylofuranose (1) and selective acetalation gave the desired isopropylidene 5-thioxylopyranose precursor 3. Acetylation and isopropylidene removal followed by benzoylation led to 3-deoxy-3-fluoro-1,2-di-Ο-benzoyl-4-O-acetyl-5′-thio-d-xylopyranose (6). This was condensed with silylated thymine and selectively deacetylated to afford 1-(2′-Ο-benzoyl-3′-deoxy-3′-fluoro-5′-thio-β-d-xylopyranosyl)thymine (8). Oxidation of the free hydroxyl group in the 4′-position of the sugar led to the formation of the target 4′-keto compound together with the concomitant displacement of the benzoyl group by an acetyl affording, 1-(2′-O-acetyl-3′-deoxy-3′-fluoro-β-d-xylopyranosyl-4′-ulose)thymine (9). Benzoylation of 3 and removal of the isopropylidene group followed by acetylation, furnished 3-deoxy-3-fluoro-1,2-di-Ο-acetyl-4-O-benzoyl-5′-thio-d-xylopyranose (12). Condensation of thiosugar 12 with silylated thymine followed by selective deacetylation led to the 1-(4′-Ο-benzoyl-3′-fluoro-5′-thio-β-d-xylopyranosyl)thymine (14). Oxidation of the free hydroxyl group in the 2′-position and concomitant displacement of the benzoyl group by an acetyl gave target 1-(4′-O-acetyl-3′-deoxy-3′-fluoro-β-d-xylopyranosyl-2′-ulose)thymine (15).