A Direct and Efficient Synthesis of 5′-Deoxy-2′, 3′-

Abstract

A direct and efficient synthesis of 5′-deoxy-2′,3′-O-isopropylideneinosine, 7, from readily available inosine is described. An example of a potentially general synthesis of N -substituted-5′-deoxyadenosines from 7 is also described.     

Synthesis of 2′-Deoxy-2′ -Fluoro-D-Arabinopyranopyranosyl Nucleosides and Their 3′,4′-Seco analogues

Abstract

2′-Deoxy-2′-fluoro-D-arabinopyranosyl nucleosides were synthesized by condensation of 1,3,4-tri-O-benzoyl-2-deoxy-2-fluoro-D-arabinopyranose with the appropriate silylated bases in the presence of trimethylsilyl triflate. Scission of the 3′,4′-bond by periodate oxidation followed by sodium borohydride reduction resulted in the formation of the 3′,4′-seco analogues of the 2′-deoxy-2′-fluoro-D-arabinofuranosyl nucleosides.     

Synthesis and Incorporation of 5″-Amino- and 5′-Mercapto-5′-Deoxy-2′-O-Methyl Nucleosides Into Hammerhead Ribozymes

Abstract

Novel 5′-amino-5′-deoxy-2′-O-methyl uridine, guanosine and adenosine 3′-O-phosphoramidites 5, 11, and 20, as well as protected 5′-mercapto-5′-deoxy-2′-O-methyl uridine 3′-O-phosphoramidite 23 were synthesized from 2′-O-methyl nucleosides. These analogs were incorporated at the 5′-ends of hammerhead ribozymes to evaluate achiral bridging 5′-N- phosphoramidates and 5′-S-phosphorothioates as alternatives for non- bridging phosphorothioates commonly used for end stabilization against nucleases. Oligonucleotide synthesis and deprotection conditions were optimized for better yields of these modified ribozymes.     

Synthesis and Evaluation of 2′-Deoxy-2′-Spirodiflurocyclopropyl Nucleoside Analogs

The preparation of 2′-deoxy-2′-siprodifluorocyclopropany-lnucleoside analogs has been achieved from α-d-glucose in several steps. The key step in the synthesis was the introduction of the difluorocyclopropane through a difluorocarbene type reaction at the 2′-position. Then, a series of novel 2′-deoxy-2′-spirodifluorocyclopropanyl nucleoside analogs were synthesized using the Vorbrüggen method. All the synthesized nucleosides were characterized and subsequently evaluated against hepatitis C and influenza A virus strains in vitro.     

Synthesis and Antiviral Activity of L-2′-Deoxy-2′-up-fluoro-4′-thionucleosides

Abstract

L-2′-Deoxy-2′-up-fluoro-4′-thionucleosides were efficiently synthesized from D-xylose via L-4-thioarabitol derivative as a key intermediate and evaluated for antiviral activities against HIV-1, HSV-1,2 and HBV.     

6′-substituted and 6′,6″-disubstituted derivatives of raffinose

The reaction of 6′-chloro-6′-deoxyraffinose deca-acetate with a variety of nucleophilic anions (Br^-,I^-,N^-₃) gave the corresponding 6′-substituted raffinoses. The 6′-azide was further converted into 6′-amino-6′-deoxyraffinose, isolated as its N-acetyl derivative, and silver fluoride-induced elimination of hydrogen iodide from the 6′-iodide gave the 6′-deoxy-5′-ene. Treatment of 6′-chloro-6′-deoxyraffinose and 6′,6″-dichloro-6′,6″-dideoxyraffinose with base afforded, respectively, 3′,6′-anhydro-and 3′,6′;3″,6″-dianhydro-raffinose in high yields. In addition, the dichloride was converted into 6′,6″-diazido-6′,6″-dideoxyraffinose.     

2′-Deoxy-2′-C-trifluoromethyl β-D-Ribonucleoside Analogues: Synthesis and Antiviral Evaluations

Abstract

Hitherto unknown 2′-deoxy-2′-C-trifluoromethyl-β-D-ribonucleoside derivatives bearing the five naturally occurring nucleic acid bases have been synthesized. The compounds were tested for their activity against HIV, HBV and several RNA viruses, but they did not show significant antiviral effect.     

Synthesis and Anti-HIV Activity of 6-Substituted Purine 2′-Deoxy-2′-fluororibosides

Abstract

3′,5′-Di-O-protected 6-chloropurine arabinoside 4b was treated with diethylaminosulfur trifluoride (DAST) and subsequently deprotected with pyridinium p-toluenesulfonate to give 6-chloropurine 2′-deoxy-2′-fluororiboside 6a. The displacement with nucleophile afforded the 6-substituted congener 6b-e. Treatment of 5′-O-protected 6-chloropurine arabinoside 3c with DAST gave lyxoepoxide 7.     

Resistance Profiles of (+) 2′-Deoxy-3′-oxa-4′-thiocytidine and (-) 2′-Deoxy-3′-oxa-4′-thio-5-fluorocytidine

Abstract

Resistant variants were selected in vitro against two novel nucleoside analogues, (+) dOTC and (-) dOTFC using the HIV-1 molecular clone HXB2D. The variants obtained displayed 6.5-fold and 10-fold resistance to these compounds, respectively. Cloning and sequencing of the RT genes of the selected viruses identified two mutations, M184I for (+) dOTC and M184V for (-) dOTFC. Results with mutated recombinant clones of HXB2D confirmed the importance of these mutations in MT-4 cells. The resistance profiles of clinical samples with wild-type or 3TC-resistant phenotypes were also studied; low to moderate levels of cross-resistance were observed against the novel compounds.     

The 5′-Nor Aristeromycin Analogues of 5′-Deoxy-5′-Methylthioadenosine and 5′-Deoxy-5′-Thiophenyladenosine

To extend the potential of 5′-noraristeromycin (and its enantiomer) as potential antiviral candidates, the enantiomers of the carbocyclic 5′-nor derivatives of 5′-methylthio-5′-deoxyadenosine and 5′-phenylthio-5′-deoxyadenosine have been synthesized and evaluated. None of the compounds showed meaningful antiviral 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 Evaluation of an RNA Editing Substrate Bearing 2′-Deoxy-2′-Mercaptoadenosine

The RNA-editing adenosine deaminases (ADARs) catalyze deamination of adenosine to inosine in double stranded structure found in various RNA substrates, including mRNAs. Here we describe the synthesis of a phosphoramidite of 2 ′-deoxy-2 ′-mercaptoadenosine and its incorporation into an ADAR substrate. Surprisingly, no deamination product was observed with this substrate indicating replacing the 2 ′-OH with a 2 ′-SH at the editing site is highly inhibitory. Modeling of nucleotide binding into the active site suggests the side chain of T375 of human ADAR2 to be in proximity of the 2 ′-substituent. Mutation of this residue to cysteine caused a greater that 100-fold reduction in deamination rate with the 2 ′-OH substrate.     

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 and antiviral evaluation of thieno[3,4-d]pyrimidine C-nucleoside analogues of 2′,3′-dideoxy- and 2′,3′-dideoxy-2′,3′-didehydro-adenosine and -inosine

Several thieno[3,4-d]pyrimidine derivatives, including four hitherto unknown 2′,3′-dideoxy- and 2′,3′-dideoxy-2′,3′-didehydro-C-nucleoside analogues of adenosine and inosine have been synthesized. When evaluated in cell culture experiments against human immunodeficiency virus, none of the tested compounds exhibited any significant antiviral effect, while two of them showed some cytotoxicity.     

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).     

A Convenient and Stereoselective Synthesis of 2′-Deoxy-β-L-Ribonucleosides

Abstract

2′-Deoxy-β-L-ribonucleosides containing usual bases which are useful as synthons for modified oligodeoxyribonucleotides, were conveniently synthesized by a stereoselective glycosylation procedure. The method is suitable for large-scale preparations.     

Synthesis and Antitumor Activity of Acyl and Benzyl Types of Prodrugs of 2′-Deoxy-2′-methylidenecytidine

Abstract

For the purpose of improvement of the in vivo antitumor activity of 2′-deoxy-2′-methylidenecytidine (DMDC, 1), we synthesized its various acyl and benzyl derivatives and evaluated them for their antitumor activity against P388 murine leukemia in mice. In terms of minimum effective dose (30% increase in life span), 5′-O-stearoyl DMDC showed two-fold higher antitumor activity than DMDC on a molar basis, when intraperitoneally (i.p.) administered to mice once a day. The antitumor activities of some other acyl derivatives were almost comparable to that of DMDC, while benzyl derivatives had no antitumor activity. Results on the hydrolysis of 5′-O-acyl derivatives by porcine liver esterase showed that at least these derivatives should not be resistant to enzymatic hydrolysis for exhibiting antitumor activity. After either an i.p. or oral dose of 3′-O-benzyl DMDC, very low concentrations of blood DMDC were seen compared with those after administration of DMDC, suggesting that the inactivity of benzyl derivatives as prodrugs was due to the minimal level of DMDC in circulation after administration.     

Antileukemic Activities and Mechanism of Action of 2′-Deoxy-4′-methylcytidine and Related Nucleosides

Abstract

Antileukemic activity of several analogues containing 2′-deoxy-4′-methylcytidine and its araC counterpart were evaluated against murine leukemic P388 cells in vitro and in vivo. Both compounds showed significant cytostatic activity (both IC₅₀=0.4 μM) in vitro and the former compound administered intraperitoneally at a dose of 3 mg/kg/day × 5 showed high activity (T/C=175%) in vivo. The mechanism of action of these 5′-triphosphates on DNA polymerases in detail will be also described.     

Synthesis of 2′,3′-Dideoxy- and 3′-Azido-2′,3′-dideoxy-pyridazine Nucleosides as Potential Antiviral Agents

Abstract

The synthesis of 4-methoxy-, 4-amino-3-chloro-, and 4-amino-1-(2,3-dideoxy-B-D-glycero-pentofuranosyl)pyridazin-6-one nucleosides, 6,19 and 20 is described. The synthesis of 3,4-dichloropyridazin-6-one (10) was accomplished in 44% overall yield using bromomaleic anhydride (17) as the starting material. The condensation of the silylated base of 10 with the halogenose 12 in the presence of trimethylsilyl triflate as a catalyst afforded a mixture of3,4-dichloro-1-(3,5-di-O-p-toluoyl-2-deoxy-B-D-erythro-pentofuranosyl)pyrridazin-6-one (13) in 67% and its α-anomer 14 in 12% yield, respectively. A series of 3′-sulfonate esters were prepared to explore the synthesis of 3-chloro-4-hydroxy-1-(3-azido-2,3-dideoxy-B-D-erythro-pentofuranosyl) pyridazin-6-one (32) via 6,3-anhydronucleoside analogues. Compounds 15, 19 and 20 were evaluated against human immunodeficiency virus, human cytomegalovirus, and herpes simplex virus type 1 but were inactive.     

Synthesis and Biological Evaluation of 9-Deazaadenine 5′-Deoxy-6′,6′-Difluoro-Carbocyclic C-Nucleoside Phosphonic Acid Derivatives

The first synthetic route to 5′-deoxy-6′,6′-difluoro-carbocyclic C-nucleoside [9-deazaadenosine, (pyrrolo[3,2-d]pyrimidine)] phosphonic acids from commercially available epichlorohydrin 5 was described. The key C-C bond formation from cyclopentanone to base precursor was performed using the Knoevenagel-type condensation. Synthesized C-nucleoside phosphonic acids were tested for anti-HIV and anti-leukemic activities. They showed moderate cytotoxicity-derived anti-HIV and anti-leukemic activities.