4,552 publications from this institution
Abstract Starting with the pyrimidine derivative (I), difluorovinyluracil (VI) is synthesized as outlined in the reaction scheme.
No abstract is provided for this article.
Abstract C-acyclic nucleoside analogues of inosine and guanosine 8-[(RS)-2,3-dihydroxypropyl] imidazo [1,5-a]-1,3,5-triazin-4 (3H)-ones 6a, c, d were synthesized. The route involved the cyclization-rearrangement of 5-acylamino-5-allyl-6-amino-4,5-dihydropyrimidin-4-ones 4a-c to 8-allylimidazo [1,5-a]-1,3,5-triazin-4 (3H) ones 5a-c. 5a was transformed selectively into 5d by reductive desulfurization with highly deactivated Raney nickel. The poorly soluble compounds 5b and 5c were converted to N-2-acetylated 5f and 5g. Osmium tetroxide hydroxylation of 5d, f, g gave 6a, c, d. None of the newly synthesized C-acyclic nucleoside derivatives showed an appreciable antiviral or antitumor cell activity.
A new acyclic adenosine analogue, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], was evaluated for its efficacy in the topical treatment of experimental keratitis caused by the thymidine kinase-positive (TK+) and thymidine kinase-deficient (TK-) herpes simplex virus type 1 (HSV-1) strains. In the treatment of TK+ HSV-1 keratitis, 0.2% (S)-HPMPA eyedrops were as effective as the reference compounds, 0.2% (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 0.2% 5-(2-chloroethyl)-2'-deoxy-uridine (CEDU) eyedrops. The three compounds produced a statistically significant healing effect, as compared with placebo eyedrops. In the treatment of keratitis caused by the TK- HSV-1 strain, 0.2%BVDU and 0.2% CEDU eyedrops did not differ from placebo eyedrops, whereas 0.2% (S)-HPMPA eyedrops exerted a highly significant healing effect.
Several compounds corresponding to fragments of the schematic representation of the polymeric structure of aurintricarboxylic acid (ATA) have been prepared and tested for prevention of the cytopathic effect of HIV-1 and HIV-2 in MT-4 cell culture and HIV-1 in CEM cell culture. Both the triphenylcarbinol 3 as well as the triphenylmethane 5 were found to afford protection against the cytopathogenicity of HIV-2 in MT-4 cells and HIV-1 in CEM cells, but they were inactive against HIV-1 in MT-4 cells. Both substances were also found to inhibit syncytium formation when MOLT-4 cells were cocultured with HIV-2-infected HUT-78 cells, but were inactive in this assay against HIV-1-infected cells. When observed, the activity is generally moderate in degree of protection and requires concentrations in the 10(-4) molar range. In contrast to ATA, both of these substances were inactive when tested for prevention of the binding of the OKT4A monoclonal antibody to the CD4 receptor and also for inhibition of HIV-1 reverse transcriptase. These substances therefore appear act by a mechanism that is distinct from that of polymeric ATA. Several active and inactive structural analogues of 3 and 5 were also synthesized. The anti-HIV activity in this series seems to depend on the presence of anionic carboxylate groups, since the methyl esters 4, 6, and 12 were uniformly inactive. The diphenylmethanes 8, 14, 18, and 19 also reproducibly inhibited the cytopathic effect of HIV-1 in CEM cell culture.
Purpose This paper provides an overview of the different binding mechanisms in selective laser sintering (SLS) and selective laser melting (SLM), thus improving the understanding of these processes. Design/methodology/approach A classification of SLS/SLM processes was developed, based on the binding mechanism occurring in the process, in contrast with traditional classifications based on the processed material or the application. A broad range of commercial and experimental SLS/SLM processes – found from recent articles as well as from own experiments – was used to explain the different binding mechanism categories. Findings SLS/SLM processes can be classified into four main binding mechanism categories, namely “solid state sintering”, “chemically induced binding”, “liquid phase sintering – partial melting” and “full melting”. Most commercial processes can be classified into the latter two categories, which are therefore subdivided. The binding mechanism largely influences the process speed and the resulting part properties. Research limitations/implications The classification presented is not claimed to be definitive. Moreover some SLM/SLM processes could be classified into more than one category, based on personal interpretation. Originality/value This paper can be a useful aid in understanding existing SLS/SLM processes. It can also serve as an aid in developing new SLS/SLM processes.
Abstract For Abstract see ChemInform Abstract in Full Text.
Considering the undesirable metabolic stability of our recently identified NNRTI <b>5</b> (<i>t</i><sub>1/2</sub> = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound <b>9g</b> was endowed with remarkably improved metabolic stability in human liver microsomes (<i>t</i><sub>1/2</sub> = 2754 min), which was about 29-fold longer than that of <b>5</b> (<i>t</i><sub>1/2</sub> = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC<sub>50</sub> = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC<sub>50</sub> = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound <b>9g</b> exhibited a more stable conformation than <b>5</b> due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound <b>9g</b> was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.
