No abstract

GEORGE 1. BIRNBAUM, MIROSLAW CYCLER, and DAVID SHUGAR. Can. J . Chem. 62, 2646Chem. 62, (1984. Crystals of acyclovir belong to the space group P2,/n, and the cell dimensions are a = 25.459(1), b = 11.282 (I), c = 10.768(1) A, P = 95.16(1)". Intensity data were measured on a diffractometer and the structure was determined by direct methods. The asymmetric unit was found to contain three independent molecules of acyclovir and two molecules of water. Least-squares refinement, which included all hydrogen atoms, converged at R = 0.053 for 3970 observed reflections. In two of the molecules the side chain is partially folded, while in the third one it is fully extended. The glycosidic torsion angles are in the range 91.4-104.3". The conformational features are compared with those in other known acyclonucleosides. They are also examined in relation to the behavior of acyclonucleosides and acyclonucleotides in various enzymatic systems, including those related to antiviral activities. (1) that replacement of the ribose moiety of guanosine by an acyclic chain corresponding to the "upper" portion of the ribose ring led to an analogue, 9-[(2-hydroxyethoxy)methyl]guanine (acycloG, acyclovir, ACV), with potent antiherpes activity. Interest in this compound, now licensed for clinical use, was further enhanced by the finding that, in HSV-infected cells, its mechanism of action was due to its specific phosphorylation by the viral-encoded (but not cellular) thymidine kinase to acyclo-GMP (l), followed by further phosphorylation by cellular GMP and GDP kinases to the triphosphate, acycloGTP, which is a selective and potent inhibitor of the HSV DNA polymerase (2).

The crystal structure of metmyoglobin from yellowfin tuna (Thunnus albacares) has been determined by molecular replacement methods and refined to a conventional R factor of 0.177 for all observed reflections in the range of 6.0-1.70 A resolution. Like other myoglobins for which a high-resolution structure is available, the polypeptide chain is organized into several helices that cooperate to form a hydrophobic pocket into which the heme prosthetic group is non-covalently bound; however, the D helix observed in other myoglobins is absent in myoglobin from yellowfin tuna and has been replaced with a random coil. As well, the A helix has a pronounced kink due to the presence of Pro16. The differences in structure between this and sperm whale myoglobin can be correlated with their reported dioxygen affinity and dissociation. The structure is in agreement with reported fluorescence data which show an increased Trp14.heme distance in yellowfin tuna compared to sperm whale myoglobin.

. 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]

No abstract