A structure-based design approach to advance the allyltyrosine-based series of HIV integrase inhibitors

As of mid-2017, only one structure of the human immunodeficiency virus (HIV) integrase core domain co-crystallised with an active site inhibitor was reported. In this structure (1QS4), integrase is complexed with a diketo-acid based strand-transfer inhibitor (INSTI). This structure has been a preferred platform for the structure-based design of INSTIs despite concerns relating to structural irregularities arising from crystallographic packing effects. A survey of the current pool of 297 reported integrase catalytic core structures indicated that the anatomy of the active site in the complex structure 1QS4 exhibits subtle variations relative to all other structures examined. Consequently, the 1QS4 structure was employed for docking studies. From the docking of twenty-seven allyltyrosine analogues, a 3-point inhibitor binding motif required for activity was established and successfully utilised in the development of a tripeptide displaying an EC₅₀ value of 10 ± 5 μM in HIV infected human T-cells. Additional docking of “in-house” compound libraries unearthed a methyl ester based nitrile derivative displaying an IC₅₀ value of 0.5 μM in a combined 3′-processing and strand-transfer assay.     

Intramolecular electrophilic aromatic substitution reactions of 2-amidoacroleins: a new method for the preparation of tetrahydroisoquinolines, tetrahydro-3-benzazepines, and hexahydro-3-benzazocines

[reaction: see text]. A variety of heterocyclic ring systems can be prepared by subjecting N-aryl-substituted 5-amido-1,3-dioxins to Lewis acids. The reactions proceed via catalyzed retrocycloadditions to afford 2-amidoacroleins and concomitant regioselective electrophilic aromatic substitution reactions. The transformation is also successful using dioxins with amides that are within the incipient ring to afford the analogous lactams.     

(E)‐1‐(2′‐Deoxy‐β‐d‐ribo­furan­osyl)‐2,4‐di­fluoro‐5‐(2‐iodo­vinyl)­benzene

This analysis of the title compound, C₁₃H₁₃F₂IO₃, establishes the orientation of (E)‐5‐(CH=CH—I) as antiperiplanar (ap) to the C—C bond (5–6 position) of the 2,4‐di­fluoro­phenyl ring system, with the (E)‐5‐(CH=CH—I) H atom located in close proximity (2.17 Å) to the F4 atom of the 2,4‐di­fluoro­phenyl moiety.     

Octafluoronaphthalene–diphenylacetylene (1/1)

The structure of the title complex, C₁₀F₈·C₁₄H₁₀, comprises mixed stacks of alternating di­phenyl­acetyl­ene and octa­fluoro­naphthalene mol­ecules, both lying at inversion centres and parallel to within 8.6 (1)°, in contrast with the herring‐bone packing observed in crystals of either pure component.     

The nido–osmaboranes [2,2,2-(CO)(PPh3)2-nido-2-OsB5H9] and [6,6,6-(CO)(PPh3)2-nido-6-OsB9H13]

The structural characterization of the osmahexaborane 2-carbonyl-2,2-bis­(tri­phenyl­phosphine)-nido-2-osmahexaborane(9), [Os(B₅H₉)(C₁₈H₁₅P)₂(CO)], (I), a metallaborane analogue of B₆H₁₀, confirms the structure proposed from NMR spectroscopy. The structure of the osmadecaborane 6-carbonyl-6,6-bis­(tri­phenyl­phosphine)-nido-6-osmadecaborane(13), [Os(B₉H₁₃)(C₁₈H₁₅P)₂(CO)], (IV), is similarly confirmed. The short basal B—B distance of 1.652 (8) Å in (I), not bridged by an H atom, mirrors that in the parent hexaborane(10) [1.626 (4) Å].     

Particle circulation and oxygen mass transfer in an immobilized cell bioreactor

Two important considerations in the design of an aerobic particulate immobilized cell bioreactor are the provision of sufficient oxygen to maintain the desired metabolism of the immobilized organism, and the biomass holdup (which is proportional to the number of immobilized cell particles in the reactor). The Circulating Bed Reactor, a reactor developed for use with those forms of immobilization that result in particles of essentially neutral buoyancy, operates with an expanded bed of circulating particles. The particle number density attainable in such a reactor has been found to be dependent upon the circulation cell aspect ratio, the individual particle properties, the static bed voidage of the particles, and the superficial gas velocity. The oxygen mass transfer characteristics have been found to be dependent upon the circulatory nature of the system, the particle (solids) holdup, the particle porosity, and the superficial gas velocity.     

DNA-PROTEIN CROSSLINKING IN NORMAL HUMAN SKIN FIBROBLASTS EXPOSED TO SOLAR ULTRAVIOLET WAVELENGTHS

Three normal human skin fibroblast cell lines were exposed to the simulated solar UV radiation produced by a fluorescent sunlamp under conditions in which the wavelength components shorter than either 295, 305 or 315 nm were excluded. The level of DNA-protein crosslinks (DPC) was then measured in those cells using the alkaline elution technique either immediately after irradiation or following a 24 h incubation. In each case, cells were exposed to fluences that induce similar levels of DPC. For cells exposed to 10 kJ m(-2) of sunlamp UV > 295 nm, the level of DPC exhibited a 2-5-fold increase following incubation. In contrast, 40-100% of the DPC were removed upon incubation of cells irradiated with either 100 kJ m(-2) of sunlamp UV > 305 nm or 150 kJ m(-2) of sunlamp UV > 315 nm. A major difference between the effects induced by these wavelength regions is that, in addition to DPC, a very high level of pyrimidine dimers is also produced by sunlamp UV > 295 nm, whereas much lower dimer yields result from treatment with either sunlamp UV > 305 nm or sunlamp UV > 315 nm. A potential role for type II DNA topoisomerase in the formation of these DPC resulting from either the change in conformational structure caused by the presence of a high level of dimers or an involvement of this enzyme in dimer excision repair is discussed.     

Multivariate Analysis of Electron Detachment Dissociation and Infrared Multiphoton Dissociation Mass Spectra of Heparan Sulfate Tetrasaccharides Differing Only in Hexuronic acid Stereochemistry

The structural characterization of glycosaminoglycan (GAG) carbohydrates by mass spectrometry has been a long-standing analytical challenge due to the inherent heterogeneity of these biomolecules, specifically polydispersity, variability in sulfation, and hexuronic acid stereochemistry. Recent advances in tandem mass spectrometry methods employing threshold and electron-based ion activation have resulted in the ability to determine the location of the labile sulfate modification as well as assign the stereochemistry of hexuronic acid residues. To facilitate the analysis of complex electron detachment dissociation (EDD) spectra, principal component analysis (PCA) is employed to differentiate the hexuronic acid stereochemistry of four synthetic GAG epimers whose EDD spectra are nearly identical upon visual inspection. For comparison, PCA is also applied to infrared multiphoton dissociation spectra (IRMPD) of the examined epimers. To assess the applicability of multivariate methods in GAG mixture analysis, PCA is utilized to identify the relative content of two epimers in a binary mixture.