A New Synthesis of 2′,3′-Didehydro-3′-deoxy-3-Alkylthymidine

Abstract

The preparation of 3-alkyl D4T derivatives has been carried out starting from the corresponding 5′-O-t-butyldimethylsilyl-3′-O-methanesulfonylthymidine 2 by way of deprotection-elimination and succesive alkylation reactions.     

The Synthesis of Novel Carbohydrates Amenable to the Synthesis of 2′,3′-Dideoxy-3′-Branched Nucleosides

Abstract

The facile synthesis of several substituted carbohydrates that are amenable for the preparation of 2′,3′-dideoxy-3′-hydroxymethyl nucleosides are reported. Elaboration of a previously reported analog, 5-O-benzoyl-3-deoxy-3-(benzyloxy)methyl-1,2-O-isopropylidene-β-D- ribofuranose (4) has provided two 2,3-dideoxy-3-branched ribose derivatives 5-O-benzoyl-2,3-dideoxy-3-(benzyloxy)methyl-1-O-methyl-β-D-ribofuranose (7) and 1.5-di-O-benzoyl-2,3-dideoxy-3-(benzyloxy)methyl-(α,β)-D-ribofuranose (10). Due to problems involved with the separation of anomeric mixtures when these carbohydrates were condensed with an heterocycle, another versatile synthon 5-O-benzoyl-3-deoxy-3-(benzyloxy)methyl-2-O-t-butyldimethylslyl-1-O- methyl-β-D-ribofuranose (12) was synthesized. The utility of this compound (12) is demonstrated in the total synthesis of 1-[3-deoxy-3-hydroxymethyl-β-D-ribofuranosyl]thymine (20).     

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 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 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 2′,3′-Didehydro-2′,3′-Dideoxy-3′-C-Methyl Substituted Nucleosides

Abstract

1-(2,3-Dideoxy-3-C-hydroxmethyl-β-D-threo-pentofuranosyl) -,1- (2,3-didehydro-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl) -and 1-(3-C-azidomethyl-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl)uracil, thymine and cytosine were synthesized and evaluated for anti-HIV activity. The synthetic strategy was based on an allylic alcohol transposition of the corresponding 3′-C-methylene-nucleoside analogues.     

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 antiviral evaluation of α-d-2′,3′-didehydro-2′,3′-dideoxy-3′-C-hydroxymethyl nucleosides

We have identified a selective S_N2′ reaction triggered by iodide ion that leads to the ring-opening of 2,2′-anhydro-α-nucleosides. By applying the method, we have synthesized α-d-2′,3′-didehydro-2′,3′-dideoxy-3′-C-hydroxymethyl nucleosides, designed as potential antiviral agents.     

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 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.     

Acyclic Nucleoside Analogues: III. A Synthesis of New 2′,3′-Dideoxy-2′,3′-Didehydronucleoside Analogues

The coupling of 5-acetoxy-1,1-dimethoxypent-2-ene with cytosine and thymine trimethylsilyl derivatives, as well as the reaction of 5-acetoxy-1-bromopent-2-ene with adenine sodium salt, yielded acyclic analogues of the corresponding nucleosides containing 5-acetoxy groups. They were deprotected with a saturated methanolic solution of ammonia to the target analogues of nucleosides, which were characterized with ¹H NMR, IR, and UV spectra.     

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.     

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.     

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 Biological Evaluation of Polyaminated 2′,3′-Dideoxy-3′-thiacytidine Prodrugs

Abstract

The syntheses and biological evaluation of polyaminated 2′,3′-dideoxy-3′-thiacytidine have been performed. A new lead was found to increase the in vitro antiviral potency (syncitia formation on MT-4 cell line) of two order magnitude greater than the parent nucleoside drug. Moreover, the in vitro activity on HIV macrophages was found to be more than 3 log greater than the activity of the parent drug 1.     

An Improved Synthesis of 2′,3′-Dideoxycytidine

Abstract

A convenient synthesis of 2′,3′-dideoxycytidine (ddC, 6) from 2′-deoxycytidine (1) has been achieved employing a base-catalyzed elimination of 3′-O?methanesulfonyl group as the key step.     

Convenient Synthesis of 4-C-Branched Lactones and 3′-C-Branched 2′,3′-Dideoxynucleosides

Abstract

The regio- and stereoselective photocatalysed addition of 2-propanol and cyclopentanol to (5S)-hydroxymethylfuran-2(5H)-one (1) gave 4-C-branched lactones 2 and 3 after selective silylations. The lactones 2 and 3 were radically deoxygenated affording lactones 4 and 5, respectively. As an example, compound 2 was transformed without purification of the intermediates into an anomeric mixtures of deprotected 3′-C-branched 2′, 3′-dideoxynucleosides 6 by the following reaction sequence: silylation, reduction, acetylation, coupling with silylated thymine and desilylation.