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The reaction scheme, developed for the synthesis of the gliotoxin analogue 2, was found to be of general applicability for analogues with varying substituents at N(1) and C(2). Analogues 11b-g prepared by this method are inhibitors of reverse transcriptase (RNA-directed DNA polymerase). Their inhibitory activity seems to be related to the lipophilicity of the effector molecules: the most lipophilic compound is the most active inhibitor. The techniques of reversed-phase thin-layer chromatography with silylated, precoated plates as well as reversed-phase high-performance liquid chromatography were used to measure the relative lipophilicities; both techniques gave analogous results.
Human papillomavirus (HPV) induced epithelial cell proliferation is responsible for a broad range of lesions. Treatment of such lesions is characterized by a high relapse rate. Four patients are described who were treated locally with cidofovir (cream 1% or injection of 2.5 mg/ml solution) for multi-treated relapsing HPV-associated lesions. Three of the four patients had a complete response. The fourth patient showed a clinical response in the first cycle of treatment, but new lesions appeared during four successive cycles of cidofovir.
Recently, we have demonstrated that T30695, a G-tetrad-forming oligonucleotide, is a potent inhibitor of human immunodeficiency virus, type I (HIV-1) integrase and the K(+)-induced loop folding of T30695 plays a key role in the inhibition of HIV-1 integrase (Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992-34999). Here we have modified T30695 by introducing a hydrophobic bulky group, propynyl dU, or a positively charged group, 5-amino dU, into the bases of T residues of the loops, and by substitution of the T-G loops by T-T loops. Physical measurements have demonstrated that the substitution of propynyl dU or 5-amino dU for T in the T residues of the loops did not alter the structure of T30695, and these derivatives also formed an intramolecular G-quartet structure, which is an essential requirement for anti-HIV activity. Measured IC(50) and EC(50) values show that these substitutions did not induce an apparent decrease in the ability to inhibit HIV-1 integrase activity and in the inhibition of HIV-1 replication in cell culture. However, the substitution of T-T loops for T-G loops induced a substantial decrease in both thermal stability and anti-HIV activity. The data analysis of T30695 and the 21 derivatives shows a significant, functional correlation between thermal stability of the G-tetrad structure and the capacity to inhibit HIV-1 integrase activity and between thermal stability of the G-tetrad structure and the capacity to inhibit HIV-1 replication, as assessed with the virus strains HIV-1 RF, IIIB, and MN in cell culture. This relationship between thermostability and activity provides a basis for improving the efficacy of these compounds to inhibit HIV-1 integrase activity and HIV-1 replication in cell culture.
No abstract is provided for this article.
Selective laser melting (SLM) is used to manufacture dense NiTi parts. The microstructure and texture are assessed (before and after annealing followed by furnace cooling) and linked to the compression behaviour and shape memory response. It is shown that SLM strongly orients the fine austenite subgrains towards the building direction. This texture induces the highest spring back along the building (vertical) direction and the lowest along the horizontal direction after compression. The compressive stiffness, on the other hand, is the highest along horizontal direction and the lowest in vertical direction. The internal stresses due to SLM processing are another factor that may induce large martensite plates, decreasing the spring back. Although post-annealing (followed by furnace cooling) annihilates these large SLM stress-induced martensite plates, it is unsuccessful to achieve completely isotropic properties. The furnace cooling after annealing may even segregate austenite and martensite within SLM solidified tracks, causing a mixed shape memory response.
A series of novel 2,3-disubstitutedquinazolin-4(3H)-ones have been synthesized by condensation of 2-substituted benzo[1,3]oxazine-4-ones and anthranilic acid. Synthesized compounds were evaluated for in vitro antiviral activity against HIV, HSV and vaccinia viruses. 5-Bromo-2-(6-bromo-4-oxo-2-phenyl-4H-quinazolin-3-yl)-benzoic acid (MBR2) exhibited distinct antiviral activity against Herpes simplex and vaccinia viruses.
Additive Manufacturing (AM) is one of the innovative technologies to fabricate components, parts, assemblies or tools in various fields of application due to its main characteristics such as direct digital manufacturing, ability to offer both internal and external complex geometries without additional cost, and the potential of varying materials at the voxel level. However, despite high anticipations, AM as a real revolution for serial production of metal components has yet to be seen, mostly due to lacks of fundamental understanding, design engineering tools, and the global robustness of the value chains. This paper aims to provide a vision about the future of metal AM based on the collective knowledge of all ten scientific and technical committees of the International Academy of Production Engineering (CIRP).
