Synthesis and biological activity of several amino analogs of thymidine

Lin, Tsung‐I; Prusoff, William H.

doi:10.1021/jm00199a020

Cited by 187 publications

(59 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3'-Azido-3'-deoxythymidine (AZT, BW A509U) was first synthesized by Horwitz et al (1) and later, by a modification of this procedure, by Lin and Prusoff (2). The antiviral activity of AZT was first reported by Ostertag et al (3) and Dube et al (4) who found a dramatic decrease of Friend virus (FV) in rnurine erythroleukernia cells previously transformed by the FV complex, whereas AZT had only a minimal effect on the replication of the host cell.…”

Section: Introductionmentioning

confidence: 99%

Structure and conformation of 3′-azido-3′-deoxythymidine (AZT), an inhibitor of the HIV (AIDS) virus

Birnbaum¹,

Giziewicz²,

Gabe³

et al. 1987

Can. J. Chem.

Self Cite

View full text Add to dashboard Cite

. 65, 2135 (1987).3'-Azido-3'-deoxythymidine (AZT), an inhibitor of HIV (human immunodeficiency virus) replication, was recently found to improve the condition of patients suffering from AIDS (acquired immunodeficiency syndrome) or ARC (AIDS-related complex). An X-ray analysis of AZT was undertaken in order to determine the three-dimensional structure of this thymidine analogue. The crystals belong to the monoclinic space group P2, and the cell dimensions are a = 5.6282(4), b = 12.0130(7), c = 17.5072(10) A, P = 95.946(5)". The structure was determined by direct methods and refined to R = 0.028 for 2029 observed reflections. Two crystallographically independent molecules were found in the asymmetric unit. One of them, molecule A, adopts a conformation which is fairly common in nucleosides, viz. a C2' endolC3' exo pucker of the furanose ring and a glycosidic torsion angle XCN = 53.4'. However, the conformation of molecule B is highly unusual. The sugar ring pucker is C3' exolC4' endo and xcN = 2.3'. This high-energy conformation may represent the biologically active form of AZT.Its determination may therefore assist in the design of other inhibitors of HIV. GEORGE I. BIRNBAUM, JERZY GIZIEWICZ, ERIC J. GABE, TAI-SHUN LIN et WILLIAM H. PRUSOFF. Can. J. Chem. 65, 2135Chem. 65, (1987.I1 a Ct C rCcemment decouvert que l'azido-3' dCoxy-3' thymidine (AZT), un inhibiteur de la rCplication du VIH (virus immunodCficitaire humain), amCliore la condition des patients soufrant du SlDA (syndrome de l'imrnuno-dCficience acquise) ou du SAS (syndrome associe au SIDA). On a entrepris une Ctude par diffraction des rayons-X du AZT dans le but de dtterminer la structure tridimensionnelle de cet analogue de la thymidine. Les cristaux appartiennent au groupe d'espace monoclinique P2, et les dimensions de la maille sont a = 5,6282(4), b = 12,0130(7) et c = 17,5072(10) A et P = 95,946(5)'. On a dCterminC la structure par des mCthodes directes et on l'a affinee jusqu'a une valeur de R = 0,028 pour 2029 reflexions observkes. On a trouvk que l'unitt asymetrique contient deux molCcules qui sont independantes d'un point de vue cristallographique. L'une d'elles, la molCcule A, adopte une conformation qui est assez commune dans les nuclCosides, soit un plissement C2' endolC3' exo du noyau furannose et un angle de torsion glycosidique xcN = 53,4O. Toutefois, la conformation de la molCcule B est assez inusitte. Le noyau de sucre subit un plissement C3' exolC4' endo et xcN = 2,3O. Cette conformation de haute Cnergie pourrait s'avCrer &tre la forme biologiquement active de 1'AZT. La determination de la configuration de 1'AZT peut donc aider au dtveloppement d'autres inhibiteurs du VIH.[Traduit par la revue]

show abstract

Section: Introductionmentioning

confidence: 99%

Structure and conformation of 3′-azido-3′-deoxythymidine (AZT), an inhibitor of the HIV (AIDS) virus

Birnbaum¹,

Giziewicz²,

Gabe³

et al. 1987

Can. J. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Such a strategy has been successfully used for the treatment of conditions such as cancer, obesity, and osteoporosis, as well as others (1). For example, zidovudine (AZT), which is clinically approved for the treatment of HIV infection, was originally developed as an anticancer drug (20,24). Thus, to expedite the development of novel anti-HIV drugs, we examined clinically approved drugs for the ability to inhibit HIV infectivity.…”

mentioning

confidence: 99%

Exploiting Drug Repositioning for Discovery of a Novel HIV Combination Therapy

Clouser

Patterson

Mansky

2010

J Virol

View full text Add to dashboard Cite

The development of HIV drugs is an expensive and a lengthy process. In this study, we used drug repositioning, a process whereby a drug approved to treat one condition is used to treat a different condition, to identify clinically approved drugs that have anti-HIV activity. The data presented here show that a combination of two clinically approved drugs, decitabine and gemcitabine, reduced HIV infectivity by 73% at concentrations that had minimal antiviral activity when used individually. Decreased infectivity coincided with a significant increase in mutation frequency and a shift in the HIV mutation spectrum. These results indicate that an increased mutational load is the primary antiviral mechanism for inhibiting the generation of infectious progeny virus from provirus. Similar results were seen when decitabine was used in combination with another ribonucleotide reductase inhibitor. Our results suggest that HIV infectivity can be decreased by combining a nucleoside analog that forms noncanonical base pairs with certain ribonucleotide reductase inhibitors. Such drug combinations are relevant since members of these drug classes are used clinically. Our observations support a model in which increased mutation frequency decreases infectivity through lethal mutagenesis.

show abstract

“…PFA was provided by Astra ALab, Sodertalje, Sweden. AZT and AZT-TP were synthesized and purified in our laboratory according to previously described methods (22,41,44). The purity of AZT and AZT-TP was established by reverse-phase and anion-exchange high-performance liquid chromatography methods and spectrophotometric analysis.…”

mentioning

confidence: 99%

Combinations of 3'-azido-3'-deoxythymidine (zidovudine) and phosphonoformate (foscarnet) against human immunodeficiency virus type 1 and cytomegalovirus replication in vitro

Eriksson

Schinazi

1989

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Combinations of 3'-azido-3'-deoxythymidine and phosphonoformate produced a moderate synergistic inhibitory effect against human immunodeficiency virus type 1 in vitro at concentrations that are easily achieved in humans. The synergistic effect was more pronounced with increasing concentrations and was not secondary to toxic effects of the drugs. 3'-Azido-3'-deoxythymidine neither inhibited the replication of human cytomegalovirus in human embryonic lung fibroblasts nor interfered with the anticytomegalovirus effect of phosphonoformate. By using partially purified reverse transcriptase of human immunodeficiency virus type 1 and human cytomegalovirus DNA polymerase, various combinations of 3'-azido-3'-deoxythymidine-5'-triphosphate and phosphonoformate produced strong indications of additive interactions. The synergistic interactions in infected cells and the additive effects observed at the reverse transcriptase level indicate that mechanisms other than the reverse transcriptase may be of importance for the inhibition of human immunodeficiency virus replication by these two compounds. A concomitant treatment of cytomegalovirus infections, such as cytomegalovirus retinitis, with phosphonoformate in patients with acquired immunodeficiency syndrome receiving 3'-azido-3'-deoxythymidine may be appropriate, and this combination may also be useful in controlling human immunodeficiency virus infection.

show abstract

Synthesis and biological activity of several amino analogs of thymidine

Cited by 187 publications

References 0 publications

Structure and conformation of 3′-azido-3′-deoxythymidine (AZT), an inhibitor of the HIV (AIDS) virus

Structure and conformation of 3′-azido-3′-deoxythymidine (AZT), an inhibitor of the HIV (AIDS) virus

Exploiting Drug Repositioning for Discovery of a Novel HIV Combination Therapy

Combinations of 3'-azido-3'-deoxythymidine (zidovudine) and phosphonoformate (foscarnet) against human immunodeficiency virus type 1 and cytomegalovirus replication in vitro

Contact Info

Product

Resources

About