Dideoxypyrimidine Nucleosides Research Articles

ChemInform Abstract: A New Class of Pyrimidine Nucleosides: Inhibitors of Hepatitis B and C Viruses.

AbstractNovel dideoxy pyrimidine nucleosides possessing a 4′‐carboxyl function are synthesized and recognized to be inhibitors of HBV and / or HCV replication.

A new class of pyrimidine nucleosides: inhibitors of hepatitis B and C viruses

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major health threats worldwide leading to liver cirrhosis, liver cancer and mortality. Herein, we report a new category of dideoxy pyrimidine nucleosides possessing a 4′-carboxyl (or carboxymethyl) function (7–9, 13, 16, 17), which are discovered as potential antiviral agents. For the first time, these nucleosides are recognized to be inhibitors of HBV and/or HCV replication. Among 4′-carboxy compounds, 3′,4′-didehydrothymidine (16) was most effective against DHBV, HBV and HCV. Modification of the 4′-position in compound 7 from a carboxyl to carboxymethyl group (17) did not affect the anti-HBV activity but greatly increased the anti-HCV activity. Importantly, 17 yielded synergistic antiviral effect when combined with ribavirin without toxicity. The activity exhibited by a single agent towards both hepatitis viruses and no detectable in vitro cytotoxicity make this new class of compounds of interest.

ChemInform Abstract: Synthesis and anti‐HIV Evaluation of 3′‐Triazolo Nucleosides.

AbstractA series of title compounds of type (I) and (II) are tested for their anti‐HIV activities.

Synthesis and Anti-HIV Evaluation of 3′-Triazolo Nucleosides

A series of hitherto unknown 3′-α-[1,2,3]-substituted triazolo-2′,3′-dideoxypyrimidine nucleoside analogues of the anti-HIV 3′-azido-3′-deoxythymidine (AZT) were synthesized through catalyzed alkyne-azide 1,3-dipolar cycloaddition (Huisgen reaction). Those 3′-[1,2,3]-triazolo analogues bearing an azido alkyl chain were evaluated for their anti-HIV activity against HIV-1 in primary human lymphocytes as well as for their cytotoxicity in different cells. None of them inhibit HIV replication (EC50 > 20 μM); two of them were converted to their triphosphate form to evaluate their HIV-RT inhibition.

ChemInform Abstract: Synthesis and Anti-HIV Activity of Several 2′-Fluoro-Containing Pyrimidine Nucleosides.

Several 2'-fluoroarabino-2',3'-dideoxy- and 2'-fluoro-2',3'-unsaturated 2',3'-dideoxy pyrimidine nucleoside analogues are reported. The saturated analogues 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)thymine (2'-threo-FddT, 33), 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)uracil (2'-threo-FddU, 22) were readily prepared from the corresponding 2'-deoxy-2'-fluoroarabinosyl nucleoside analogue by radical deoxygenation of the 3'-OH. The unsaturated compounds 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2-enofuranosyl)thymine (2'-Fd4T, 40) and 1-[5-O-(mono-methoxytrityl)-2-fluoro-2,3-dideoxy-beta-D-glycero-pen t-2- enofuranosyl]uracil (39) were synthesized by an elimination reaction of the O-2,3'-anhydro-2'-fluoro-lyxo derivatives under basic conditions. The cytidine analogues 28 and 41 were prepared by amination of the corresponding uridine derivatives; compounds 28 and 41 were deprotected to give 1-(2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)cytidine (2'-threo-FddC, 29) and 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2- enofuranosyl)cytosine (2'-Fd4C, 42), respectively. All of these novel compounds were evaluated in vitro against human immunodeficiency virus (HIV) (LAV isolate). 2'-threo-FddC (29) was the most active of the newly synthesized substances against HIV with an ID50 of 0.8 microgram/mL; ddC had an ID50 of 0.007 micrograms/mL. Because of its potency in the initial tests, 29 was further evaluated in both T cells and macrophage/monocyte cell lines, with several different isolates of HIV. Although 2'-threo-FddC (29) exhibited good antiviral activity in these systems it was less active than AZT in these assays. At 1 microM the inhibition of CFU-GM by 29 was found to be 35-40%; this is slightly higher than seen with AZT.

New 5-Modified Pyrimidine Nucleoside Inhibitors of Mycobacterial Growth

The WHO has declared tuberculosis (TB) a global health emergency. Therefore, there is an urgent need to discover and develop new anti-TB drugs. Here we report a new category of 5-substituted pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis growth in vitro. A series of 2'-deoxy-, 3'-azido-2',3'-dideoxy-, and 3'-amino-2',3'-dideoxypyrimidine nucleoside analogues bearing lengthy flexible alkyloxymethyl substituents exhibited marked inhibitory activity against M tuberculosis in vitro. 5-Dodecyloxymethyl-2'-deoxyuridine was found to be a potent inhibitor of M. tuberculosis propagation in vitro. In contrast, monophosphates of the tested nucleosides were devoid of antimycobacterial activity. This new class of inhibitors seems to be a promising chemotherapeutic agent against TB and merits further studies.

New 5-Modified Pyrimidine Nucleoside Inhibitors of Mycobacterial Growth

The WHO has declared tuberculosis (TB) a global health emergency. Therefore, there is an urgent need to discover and develop new anti-TB drugs. Here we report on a new category of 5-substituted pyrimidine nucleosides as potent inhibitors of Myco-bacterium tuberculosis growth in vitro. A series of 2'-deoxy-, 3'-azido-2',3'-dideoxy-, and 3'-amino-2',3'-dideoxypyrimidine nucleoside analogues bearing lengthy flexible alkyloxymethyl substituents exhibited marked inhibitory activity against M. tuberculosis in vitro. 5-Dodecyloxymethyl-2'-deoxyuridine was found to be a potent inhibitor of M. tuberculosis propagation in vitro. In contrast, monophosphates of the tested nucleosides were devoid of antimycobacterial activity. This new class of inhibitors seems to be a promising chemotherapeutic agent against TB and merits further studies.

Structural Determinants of HIV-1 Reverse Transcriptase Stereoselectivity Towards (β)-L-Deoxy- and Dideoxy-Pyrimidine Nucleoside Triphosphates: Molecular Basis for the Combination of L-Dideoxynucleoside Analogs with Non-nucleoside Inhibitors in Anti HIV Chemotherapy

We have compared the HIV-11 RT mutants containing the single substitutions L100I, K103N, V106A, V179D, Y181I and Y188L, known to confere NNI-resistance in treated patients, to HIV-1 RT wt for their sensitivity towards inhibition by D- and L-deoxy- and dideoxy-nucleoside tiphosphates. The results showed a differential effect of the substitutions on the affinity for both D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphates and provide a rationale for the utilization of L-dideoxynucleoside analogs with NNI in combination chemotherapy.

Stereospecific synthesis of 2′-deoxy pyrimidine and 5,6-dihydro 5-hydroxy thymidine nucleosides

An economic and versatile synthesis of 2′-deoxy and 2′,3′-dideoxy pyrimidine nucleosides is described. Readily available oxazoline 1 is condensed with glycidate 2 to give anhydro nucleoside 3. This is converted to the title compounds following established routes.

Conformational comparative analysis of pyrimidine nucleoside derivatives by molecular mechanics calculations and by semiempirical methods (AM1)

A conformational comparative analysis of some 2′ and 2′,3′-dideoxypyrimidine nucleosides 4′-substituted analogues was carried out by molecular mechanics and molecular orbital calculations. The influence of modifications at the C6 of the pyrimidine ring with respect to the relative position of the glycosidic link has been studied by both methods. The charge distribution of these compounds was calculated by the semiempirical method neglect of diatomic differential overlap.

Selective protection of toxicity of 2′,3′-dideoxypyrimidine nucleoside analogs by β- d-uridine in human granulocyte-macrophage progenitor cells

β- d-Uridine protected human granulocyte-macrophage lineage cells in both semi-solid (granulocyte-macrophage colony-forming units, CFU-GM) and liquid cultures against the toxic effects of 3′-azido-3′-deoxythymidine (AZT), 3′-fluoro-3′-deoxythymidine (FLT) and a combination of AZT and FLT, without impairment of the activities of these respective drugs against human immunodeficiency virus (HIV) replication. In addition, β- d-uridine also protected human CFU-GM against toxicity of the in vivo AZT metabolite, 3′-amino-3′-deoxythymidine (AMT). β- l-uridine and α- d-uridine, two stereoisomers of the natural form, and the base uracil, were unable to protect cells against either AZT or FLT toxicity, whereas β- d-uridine-5′-bis(SATE)phosphotriester, a prodrug of β- d-uridine-5′-monophosphate, successfully protected cells against AZT toxic effects, suggesting that β- d-uridine needs to be metabolized to its nucleotides to exert a pharmacological effect. These data suggest in addition that AZT, FLT and AMT share a common target site(s) of toxicity involved in myelosuppression.

Protection and rescue from 2',3'-dideoxypyrimidine nucleoside analog toxicity by hemin in human bone marrow progenitor cells.

Long-term therapy of AIDS patients with 3'-azido-3'-deoxythymidine (AZT) remains of concern because of resulting hematopoietic toxicity. While the mechanism(s) of this toxicity remains elusive, alternative strategies are being developed to reduce these toxic effects, including combination therapy with nonmyelotoxic antihuman immunodeficiency virus drugs and/or administration of protective or rescue agents, including cytokines and growth factors. By using a particularly relevant human CD34+ liquid culture system, the unique profiles of dideoxynucleoside (ddN) toxicities to both proliferation and differentiation were demonstrated, with decreased potencies in the order of 3'-fluoro-3'-deoxythymidine (FLT) = 3'-amino-3'-deoxythymidine (AMT) = 2',3'-dideoxycytidine > AZT for inhibition of proliferation and in the order of FLT = AMT > AZT >> 2',3'-dideoxycytidine for inhibition of hemoglobin synthesis. Hemin selectively protected erythroid-lineage human burst-forming unit-erythroid cells from AZT- and AMT-induced inhibition but had no effect on FLT toxicity under similar conditions. Myeloid-lineage human CFU-granulocyte-macrophages were also not protected by hemin against all three ddN analogs. The simultaneous exposure of cells to hemin and AZT resulted in a complete protection of both cell proliferation and hemoglobin synthesis. In contrast, in reversal studies only the inhibition of the percentage of hemoglobin-synthesizing cells returned to control levels, but the inhibition of proliferation of cells previously exposed to AZT was not reversed by hemin. These studies further define the unique and multifactorial mechanism(s) of ddN-induced toxic effects during hematopoietic development of pluripotent stem cells and suggest that the use of hemin could be beneficial in alleviating the toxicity of certain ddN analogs.

Aqueous molecular dynamics simulations of eight modified 2',3'-dideoxypyrimidine nucleosides

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAqueous molecular dynamics simulations of eight modified 2',3'-dideoxypyrimidine nucleosidesDirk H. Everaert and Camiel J. De RanterCite this: J. Am. Chem. Soc. 1993, 115, 24, 11209–11212Publication Date (Print):December 1, 1993Publication History Published online1 May 2002Published inissue 1 December 1993https://doi.org/10.1021/ja00077a019RIGHTS & PERMISSIONSArticle Views84Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (820 KB) Get e-Alerts Get e-Alerts

Absolute Configuration of the Antiviral Agent (−)-cis-5-Fluoro-1-[2-Hydroxymethyl)-1,3-Oxathiolan-5-yl]Cytosine

The structure and absolute configuration of (−)- cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (FTC), has been determined by X-ray crystallographic analysis. The results confirm that the L-isomer of the nucleoside analogue is the most active enantiomer and that the correct absolute configuration of (−)-FTC is 5-fluoro-(2′R,5′S)-(−)-1-[2-hydroxymethyl)oxathiolan-5-yl]-fluorocytosine. The two molecules in the asymmetric unit show conformations that combine conformational features of two other classes of potent antiviral nucleosides. Both oxathiolane rings have the 3′-sulphur atom in nearly perfect S3′- exo envelope conformations, similar to what is observed for 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxycytidine. One of the two molecules has a glycosylic link conformation in which the base is eclipsed with the C5′-O1′ bond. This mimics the high- anti conformation that has been observed in the structures of several 2′,3′-didehydro-2′,3′-dideoxypyrimidine nucleosides but is inaccessible for saturated pyrimidine nucleosides. However, the observed conformations cannot be superimposed adequately with other active antiviral nucleosides to suggest a common ‘active site’ conformation.

Conformational Analysis of Substituent Effects on the Sugar Puckering Mode and the anti-HIV Activity of 2′,3′-Dideoxypyrimidine Nucleosides

A comparison between the conformational parameters of eleven active and inactive anti-HIV 2′,3′-dideoxypyrimidine nucleosides and a series of 73 uridine and thymidine structures, revealed that our compounds, all having N-glycosidic bond torsion angles χ in the anti range, have pseudorotation phase angles P well distributed over both N (C3′- endo) and S [C2′- endo and C3′- exo) type sugar conformations and have both + sc and ap C4′-C5′ conformations. This means that solid state conformations characterized by P, χ and γ do not provide decisive information for predicting possible anti-HIV activity. We also found that any rationalization of the activity or inactivity of nucleosides in terms of the gauche effect of electronegative substituents on the furanose ring conformation, could not be demonstrated by using the semiempirical quantum chemical AM 1 method. Calculations of C3′-X3′ bond polarities indicate that anti-HIV activity in C3′-substituted nucleoside analogues is consistent with the presence of a positive C3′-X3′ bond polarity. Exploration of the conformational space of χ vs. γ for C3′- endo, C2′- endo and C3′- exo sugar puckering modes using the same AM1 method, reveals that although the C3′- endo [ P = 10°) region is about 2 kcal mol−1 lower than the C2′- endo region ( P = 170°), the C2′ - endo sugar puckering mode is the most accessible one due to the conformational flexibility about the minima. Our results also suggest that as P increases from 10°, through 170°, to 210°, the preferred range for -y dramatically shifts from almost exclusively around 50° (+ sc) at P = 10° to almost exclusively non + sc at P = 210°.

Conformational analysis of 2',3'-didehydro-2',3'-dideoxypyrimidine nucleosides

The molecular conformations of 2',3'-didehydro-2',3'-dideoxypyrimidine nucleosides have been studied by X-ray crystallographic analysis and molecular mechanics calculations. In this paper, the crystal structures of the uridine, cytidine, and 5-ethyluridine analogues are reported. The structures of two crystal forms of the thymidine analogue and another crystal form of the cytidine analogue that were reported elsewhere (Gurskaya et al. Int. J. Purine Pyrimidine Res. 1991, 2, 55-60. Harte et al. Biochem. Biophys. Res. Commun. 1991, 175, 298-304. Birnbaum et al. Nucleosides Nucleosides 1989, 8, 1259-1269.) are included in the analysis

Synthesis of various 3'-branched 2',3'-unsaturated pyrimidine nucleosides as potential anti-HIV agents

A series of four new 2',3'-dideoxypyrimidine nucleosides was synthesized and their activity against HIV war evaluated. Coupling of a suitably protected 3-methylidene xylofuranose derivative 5 with thymine and uracil afforded branched nucleosides 7a and 7b. The latter war transformed into 2',3'-dideoxy-2',3'-didehydro 3'-branched nucleoside 1 by Barton deoxygenation during which an allylic rearrangement occurred

Synthesis of Novel Fluorinated 2′,3′-Dideoxynucleosides

Abstract The synthesis of various 2′,3′-dideoxypyrimidine nucleosides, starting from 5-(2,2,2-trifluoroethoxymethyl) (10) and 5-(bis-2,2,2-trifluoroethoxy)methyl-2′-deoxyuridine (11), is described. These compounds were synthesized for screening against herpes simplex virus type-1 and type-2, and HIV virus.

Computer-assisted structure-activity correlations of halodideoxynucleoside analogs as potential anti-HIV drugs.

Analysis of the structure-anti-HIV activity correlations of halo dideoxynucleosides (ddN's) in the public domain was accomplished through computer substructure searching, retrieval and sorting of in vitro anti-HIV data. In the survey, selectivity index (ratio of cytotoxicity to the potency in inhibiting HIV replication in vitro) was used to rank compounds in congeneric groups. Factors contributing to the anti-HIV activity, e.g. the nature and location of the halogen on the sugar or the base and its stereochemical configuration, could not be generalized for all the halogenated ddN's. Conclusions were drawn for specific classes within the pyrimidine and purine series, with compounds further divided into halo substitutions at the sugar 2',3',4'-positions or in the pyrimidine or purine ring systems. At the 3'-position, only a fluoro substitution enhanced the activity of the dideoxypyrimidine nucleosides. A 2'-ara fluoro substituent increased the activity of purine ddN's but decreased activity of pyrimidine ddN's. Halogenation of the side chain in acyclic adenine and 2,6-diaminopurine nucleosides improved their anti-HIV activity. Halo substitution at the 6- or 2'-ara position of selected purine ddN's resulted in compounds with increased lipophilicity, chemical stability and retention of anti-HIV activity. The number of halodideoxynucleosides tested as anti-HIV reagents suggested that this class of compounds is well studied.

A Useful Method for the Synthesis of β-2′,3′-Dideoxynucleosides via a Thioglycoside

A series of the protected β-2′,3′-dideoxypyrimidine nucleosides are synthesized stereoselectively by the coupling of phenyl 5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-1-thio-D-glycero-pentofuranoside with silyl derivatives of nucleoside bases in the presence of N-bromosuccinimide at -78 °C.