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 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 Properties of Some 2′-O-d-Ribofuranosyl-nucleosides

Abstract

A high yield preparation of 9-(2-O-β-d-ribofuranosyl-β-d-ribofuranosyl)-adenine and its pyrimidine analogues has been achieved and their physico-chemical properties were investigated.     

Oxidation Chemistry of Adenosine-3′, 5′-Cyclic Monophosphate at Pyrolytic Graphite Eletrode

The voltammetric oxidation of adenosine-3′,5′-cyclic monophosphate (3′,5′-CAMP) has been studied in the pH range 2.13–10.07 using pyrolytic graphite electrode (PGE). Voltammetric, coulometric, spectral studies, and product characterization indicate that the oxidation of 3′,5′-CAMP occurs in an EC reaction involving a 6H⁺, 6e process at pH 7.24. Electrooxidized products were seperated by semipreparative high performance liquid chromatography (HPLC) and were characterized by mp, ¹HNMR, FTIR, and GC-mass as allantoin cyclic ribose monophosphate and 3 dimers as the major products. A detailed interpretation of the redox mechanism of 3′,5′-CAMP also has been presented to account for the formation of various products.     

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).     

Synthesis and Biological Evaluation of Some 5-Nitro- and 5-Amino Derivatives of 2′-Deoxycytidine, 2′,3′-Dideoxyuridine,and 2′,3′-Dideoxycytidine

Abstract

In this article, we describe the synthesis of 5-nitro-1-(2-deoxy-α-D-erythro-pentofuranosyl)cytosine (4α), 5-nitro-1-(2-deoxy-β-D-erythro-pentofuranosyl)cytosine (4β), 5-amino-1-(2-deoxy-α-D-erythro-pentofuranosyl)cytosine (5α), 5-nitro-1- (2-deoxy-β-D-erythro-pentofuranosyl)cytosine (5β), 5-nitro-1-(2,3-dideoxy-β- D-ribofuranosyl)uracil (6β), 5-amino-1-(2,3-dideoxy-α,β-D-ribofuranosyl)uracil (7), 5-nitro-1-(2,3-dideoxy-α,β-D-ribofuranosyl)cytosine (8) and 5-amino-1-(2,3-dideoxy-β-D-ribofuranosyl)cytosine (9β). The prepared compounds were tested for their activity against HIV and HBV viruses, but they did not show significant activity.     

Synthesis of Some 2′,3′-Dideoxy-3′-C-Fluoromethyl and 3′-C-Azidomethyl Nucleosides

Abstract

The synthesis of 3′-C-fluoromethyl and 3′-C-azidomethyl nucleosides is reported. The 3′-C-fluoromethyl furanoside 4 was synthesized via fluoride ion induced displacement of the corresponding trifluoromethanesulfonate. The 3′-C-hydroxymethyl furanoside 3 was converted to the corresponding 3′-C-azidomethyl furanoside 6 using triphenylphosphine-carbon tetrabromide-lithium azide. The 3′-C-fluoromethyl furanoside derivative 5 and the 3′-C-azidomethyl furanoside derivative 7 were subsequently condensed with silylated purine and pyrimidine bases. Deblocking and separation of the anomers by chromatography afforded the α- and β-nucleoside analogues. The nucleosides were tested for inhibition of HIV multiplication in vitro and were found to be inactive in the assay.     

Synthesis and Biological Properties of the Four Optical Isomers of 5-o-Carboranyl-2′,3′-didehydro-2′,3′-dideoxyuridine

Abstract

The four isomers of the 5-o-carboranyl-2′,3′-didehydro-2′,3′-dideoxyuridine (d4CU) were synthesized and their antiviral activity and cytotoxicity in normal and cancer human cells determined. Coupling of silylated 5-o-carboranyluracil with the protected D/L 2,3-dideoxy-2-phenylselenenylribosylacetates provided after oxidative elimination and deprotection, the desired compounds. The presence of the electron deficient 5-o-carboranyl moiety on uracil influenced the yield of the various isomers. In general, the compounds demonstrated weak anti-human immunodeficiency virus activity in primary human lymphocytes. No marked difference in the biological profile was noted for the various optical isomers, suggesting that the high lipophilicity of these nucleosides imparted by the carboranyl moiety overrides stereochemical considerations in the 2′,3′-didehydro-2′,3′-dideoxy-aglycon moiety.     

Synthesis of Some 2′,3′-Dideoxy-2′-C-Methyl-Substituted Nucleosides

Abstract

Nucleoside analogues analogues1-(2′,3′-dideoxy-2′-C-hydroxymethyl-β-D-erythro-pentofuranos-yl)thymine (1), 2′,3′-dideoxy-2′-C-hydroxymethylcytidine (2), 2′,3′-dideoxy-2′-C-hydroxymethyladenosine (3), 1-(2′-C-azidomethyl-2′,3′-dideoxy-β-D-erythro-pento-furanosyl)thymine (4), 2′-C-azidomethyl-2′,3′-dideoxycytidine (5), and 2′3′-dideoxy-2′-C-methylcytidine (6) have been synthesized from (S)-4-hydroxymethyl-y-butyro-lactone (7)     

Synthesis of 3′-Fluoro-3′-Deoxyribonucleosides; Anti-HIV-1 and Cytostatic Properties

Abstract

It has generally proven difficult to synthesize ribonucleosides with sugar modifications at the 3′ position. We now present a practical route for the synthesis of ribonucleosides with a 3′ fluorine substituent. Nucleosides with the xylo configuration were prepared by sugar-base condensation. Tritylation of the unprotected nucleosides gave a mixture of 2′,5′ and 3′,5′ bistritylated nucleosides which were difficult to characterize. Therefore the necessary precursors were synthesized in a step-wise fashion, starting with selective deprotection of the 2′-acyl group, followed by tritylation. This gave the 2′,5′-tritylated xylonucleosides in good yield. Reaction with diethylaminosulfur trifluoride and deprotection with 80 % acetic acid provided the 3′-fluoro-3′-deoxyribonucleosides 1, 2 and 4. The cytidine derivative was synthesized from 1 by reaction with trifluoromethanesulfonic anhydride followed by ammonia. Treatment of 4 with adenosine deaminase yielded 5.     

Synthesis of 5′-Fluoro-5′-deoxy-and 5′-Amino-5′-Deoxytoyocamycin and Sangivamycin and Some Related Derivatives

Abstract

A series of 5′-substituted analogs of toyocamycin were prepared by condensation of silylated 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine with protected 5-azido-5-deoxy- or 5-fluoro-5-deoxyribofuranose followed by debromination and deblocking. Alternatively, 5′-azido-5′-deoxytoyocamycin was prepared by azidation of toyocamycin. Conversion of the 5-nitrile function of the toyocamycin derivatives into a carboxamide or a thiocarboxamide gave the corresponding analogs of sangivamycin or thiosangivamycin while reduction of the 5′-azido-5′-deoxy nucleosides provided 5′-amino-5′-deoxy derivatives.     

Synthesis of 2′,5′-Dideoxy-adenosine-3′-monophosphate Derivatives as Allosteric Inhibitors of Adenylyl Cyclase

Abstract

The synthesis of a fluorescent and a lipophilic conjugate of 2′,5′-dideoxy-3′-AMP, an allosteric inhibitor of adenylyl cyclase, has been devised.     

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)CH₂OH 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.     

3′, 5′-Cyclic Adenosine Monophosphate Dependent Xylose Lethal Phenomenon in Escherichia coli

The growth of Escherichia coli W2252 was found to be inhibited when xylose and cAMP coexisted in the medium such as peptone or nutrient broth. Among other sugars, only arabinose imposed weaker effect. cAMP could not be replaced by adenine, adenosine, 5′-AMP, 3′-AMP and other 3′,5′-cyclic nucleoside monophosphates. Dose response was observed with reference to either xylose or cAMP. In the presence of both 1% xylose and 10 mm cAMP in peptone broth, 90% of logarithmic phase cells of E. coli W2252 were killed within 6 hr at 37°C. We call this phenomenon as cAMP dependent xylose lethal. This phenomenon was also observed with many substrains of E. coli K–12, E. coli C, Aerobacter aerogenes and Salmonella typhimurium, but not with their xylose negative mutants.     

Stereoselective Synthesis of Ribonucleoside 3′,5′-Cyclic Methyl(phenyl)phosphonates and Phosphonothioates

Abstract

Monophosphonylation of 2′-protected ribonucleosides (i.e. 2′-O-THP-uridine and 2′-O-THP-N ⁶-levulinoyl-adenosine) with the bifunctional reagents bis[(6-trifluoromethyl)benzotriazol-1-yl] methyl(phenyl)phosphonates or the analogous phosphonothioates, and subsequent addition of N-methylimidazole, gave the chirally pure 3′,5′-cyclic methyl(phenyl)phosphonate or phosphonothioate derivatives, respectively. Deblocking of the fully protected compounds yielded, as evidenced by X-ray analysis, the corresponding pure Sp-diastereoisomers.     

Synthesis and Structure of 2′,3′-Dideoxy-3′-fluoro-5-cyanouridine

Abstract

The title compound was prepared by reaction of the 5-bromo congener with potassium cyanide in DMF. X-ray analysis revealed its solid state structure and the obtained conformation was compared to the con-formation of 3′-azido-3′-deoxythymidine (AZT) and of 2′,3′-dideoxy-3′-fluoro-5-chlorouridine, respectively, two very selective anti-HIV agents. They both show two separate molecules in their asymmetric unit, one of each fairly resembling the conformation of the title compound 4. The latter, however, displayed only very moderate activity.     

Synthesis and Anti-viral Properties of 2′,3′-Dideoxy-3′,4′-dihydroxymethyl Substituted Pyrimidine Nucleoside Analogues

Abstract

Some 2′,3′-dideoxy-3′, 4′-dihydroxymethyl nucleoside analogues have been synthesised starting from diacetone-D-glucose. The 3-C-hydroxymethyl group was introduced by selective hydroboration-oxidation of the 3-C-methylene derivative. The 4-C-hydroxymethyl group was obtained by an aldol condensation followed by in situ cross Canizzaro reduction. Glycosylation using silylated pyrimidine bases furnished the 2′,3′-dideoxy-3′,4′-dihydroxymethyl nucleoside analogues.     

Cytidine 3′,5′-Cyclic Monophosphate: A Third Cyclic Nucleotide Secondary Messenger?

Abstract

Recent evidence has now proven the natural occurrence of cyclic CMP, of specific enzymes capable of its synthesis and hydrolysis, and of cyclic CMP-binding proteins and cyclic CMP-responsive protein kinases; the effects of exogenously administered cyclic CMP are consistent with a role for cyclic CMP in the regulation of cell profliferation and/or mediation of steroid hormone actions.     

Synthesis and Evaluation of 2′,3′-Dideoxy-9-Deazaadenoslne and Some Related Derivatives

Abstract

In this paper we report the synthesis of 2′,3′-dideoxy-9-dearaadenosine (2) and the corresponding 2′,3′-unsaturated- and 3′-deoxy- analogs, 6 and 8. These C-nucleosides are very stable towards acid and thus overcome one of the main drawbacks of 2′,3′-dideoxy-purine-nucleosides, such as the antiviral agent 2′,3′-dideoxyadenosine (ddA). However, evaluation of these compounds and some related 2′-deoxy derivatives (10-14) in the antiviral assay for the human immunodeficiency virus has revealed no significant activity.     

Synthesis and Binding Properties of a Homopyrimidine 2′,5′-Linked Xylose Nucleic Acid (2′,5′-XNA)

Abstract

The synthesis and hybridization properties of pyrimidine 2′,5′-RNA and 2′,5′-Xylose Nucleic Acid (2′,5′-XNA) are described.